Amino methylated 2-pyridinones

ABSTRACT

Novel amino methylated 2-pyridinones, precursors, intermediates, and derivatives; the methods for the preparation of the same; uses of the same for inhibiting pili formation in bacteria; and pharmaceutical compositions comprising these compounds are described in this application. The present compounds may be employed to inhibit biofilm formation and thereby inhibit adherence of bacteria to a host cell.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/563,082, filed Apr. 16, 2004, and International PatentApplication Serial No. PCT/US2005/013032, filed Apr. 14, 2005, theentire content of each of which is hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

The present invention is directed to secondary and tertiary aminomethylated 2-pyridinones, to methods of their preparation and to theiruse for inhibiting pili formation in bacteria.

The core structure of 2-pyridinones, or more commonly referred to as2-pyridones, is present in a wide range of compounds with diversebiological application areas. Besides showing e.g., antibacterial,¹antifungal² and anti-tumor activity,^(3,4) members of these heterocyclesalso act as inhibitors of a Aβ-peptide aggregation thought to play animportant role in Alzheimers' disease.⁵ An enantioselective ketene iminecycloaddition reaction to synthesize ring fused substituted 2-pyridoneshas previously been reported.^(6,7) Starting from commercially availablenitrites and carboxylic acids, this synthetic pathway rendered a firstgeneration of 2-pyridones that were designed to target periplasmicescort proteins, chaperones, in uropathogenic Escherichia coli.Chaperones are essential for the assembly of adhesive protein organellesknown as pili or fimbriae present on the surface of the bacteria, inabsence of these organelles the bacteria become non-infectious.⁸ Thus,compounds interfering with pili/fimbriae formation, pilicides, wouldrepresent a novel class of antibacterial agents directed againstbacterial virulence considered a promising avenue in drug development.⁹

Encouraging affinity predictions of substituted 2-pyridones binding tothe chaperones PapD and FimC have previously been confirmed in vitro bydirect binding assays using both surface plasmon resonance techniquesand NMR spectroscopy, where the corresponding acid of 4a was found to bea potent binder.¹⁰ Recently, efficient improvements of the originalsynthetic procedure were reported.¹¹ This alternative microwave assistedmethod allows simple and fast preparation of highly substituted2-pyridones in good yields and with limited racemization. Still,position six is available for further substitution and thus provides anopportunity to introduce hydrophilic functionalities targeting increasedbioavailability and enhanced chaperone affinity in the pilicide project.Incorporation of a cyano group would provide a precursor to a number ofinteresting derivatives such as carboxylic acids,¹² tetrazoles,¹³ andamidines.¹⁴ Nitriles can also be converted into primary amines andinspired by former observations in drug development this appeared to bean attractive target. For example in the case of Ampicillin andAmoxycillin, the introduction of an amine substituent led to a broadspectrum antibiotic also affecting Gram-negatives.¹⁵ In addition,introducing amine substituents in the 2-pyridone framework would resultin highly substituted rigid amino acids, which could serve as versatilescaffolds and peptide mimetics.¹⁶

Aromatic cyanodehalogenation and subsequent reduction of the cyanofunctionality was considered a well cited and straightforward pathwaytowards amino methylated 2-pyridones.^(17,18) As a complement to theprimary amines, and to expand the chemical diversity of thesestructures, tertiary amines were also desired. A few scattered exampleswhere 2-pyridones react with imines in a Mannich reaction in thecorresponding position have previously been described^(19,20) andrecently, microwave mediated Mannich reactions performed withelectron-rich aromatic substrates have also been published.^(21,22)Nevertheless, applications on more complex structures such asfunctionalized 2-pyridones with a challenging substitution pattern havepreviously not been reported.

SUMMARY OF THE INVENTION

Among the various aspects of the present invention are secondary andtertiary amino methylated 2-pyridinones (and their corresponding salts),methods of their preparation and their use for inhibiting pili formationin bacteria.

Briefly, therefore, the present invention is directed to an aminomethylated 2-pyridinone corresponding to Formula I or a salt thereof:

wherein:

R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, heterocyclo, or in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen;

R₄ and R₅ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or heterocyclo, provided at least one of R₄ and R₅ is otherthan hydrogen; and

the “Z” ring contains 5 to 7 ring atoms selected from the groupconsisting of carbon, oxygen, nitrogen and sulfur, provided (i) at least4 of the ring atoms are carbon when the “Z” ring contains 7 ring atoms,and (ii) at least 3 of the ring atoms are carbon when the “Z” ringcontains 5 or 6 ring atoms.

The present invention is further directed to an amino methylated2-pyridinone corresponding to Formula II or a salt thereof:

wherein:

R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, heterocyclo, or in combination with the nitrogen atom towhich they are bonded, form a heterocyclo provided at least one of R₂and R₃ is other than hydrogen;

R₄ and R₅ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or heterocyclo, provided at least one of R₄ and R₅ is otherthan hydrogen;

X₁, is a bond, carbon, oxygen, nitrogen, or sulfur;

X₂ is a bond, carbon, oxygen, nitrogen, or sulfur;

X₃ and X₄ are independently carbon, oxygen, nitrogen, or sulfur;

X₅ is carbon or nitrogen;

each X₁₁, when present, is an electron pair, hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, or oxo;

each X₂₂, when present, is an electron pair, hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, or oxo;

each X₃₃ and X₄₄ is independently an electron pair, hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, or oxo;

X₅₅ is —CH₂OX₅₅₅, —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅, —CHO, —B(OH)₂,or —PO(OH)₂; and

X₅₅₅ is hydrogen or other cation, hydrocarbyl, substituted hydrocarbyl,or heterocyclo;

provided, however, (i) X₁₁ or X₂₂ is not present when X₁, or X₂ is abond; and (ii) X₁, X₂, X₃, and X₄ are not oxygen, nitrogen or sulfurwhen X₅ is nitrogen.

The present invention is further directed to a compound having theformula

wherein R1, R2, and R3, in combination, are selected from thecombinations identified in the following table as combinations 8a-8f:Combination No. R¹ R² R³ 8a phenyl methyl NMe₂ 8b phenyl methylmorpholine 8c phenyl CH₂-1-naphtyl NMe₂ 8d phenyl CH₂-1-naphtylmorpholine 8e cyclopropyl CH₂-1-naphtyl NMe₂  8f^(c) cyclopropylCH₂-1-naphtyl morpholine

The present invention is further directed to amino methylated2-pyridinones corresponding to one or more of Formulae III-VIII (whichappear elsewhere herein) or a salt thereof.

The present invention is further directed to a method for thepreparation of an amino methylated 2-pyridinone or a salt thereof, theprocess comprising forming a reaction mixture comprising a 2-pyridinoneand an iminium salt, allowing the 2-pyridinone and iminium salt to reactto form, via a Mannich reaction, an amino methylated 2-pyridinonecorresponding to any of Formulae I-VIII (which appear elsewhere herein),wherein the nitrogen atom of the amino methyl substituent is a tertiaryamine.

The present invention is further directed to a method for thepreparation of an amino methylated 2-pyridinone or a salt thereof, theprocess comprising forming a reaction mixture comprising a 2-pyridinoneand an iminium salt, allowing the 2-pyridinone and iminium salt to reactto form, via a Mannich reaction, an amino methylated 2-pyridinonecorresponding to any of Formulae I-VIII (which appear elsewhere herein),wherein the nitrogen atom of the amino methyl substituent is a tertiaryamine, and wherein the reaction mixture is irradiated with microwaves.

The present invention is further directed to a method for thepreparation of an amino methylated 2-pyridinone or a salt thereof, theprocess comprising reacting a 2-pyridinone and reducing the formylsubstituted 2-pyridinone to form an amino methylated 2-pyridinonecorresponding to any of Formulae I-VIII (which appear elsewhere herein),wherein the nitrogen atom of the amino methyl substituent is a secondaryamine.

The present invention is further directed to a process for inhibitingadherence of bacteria to a host cell, the process comprising treatingthe bacteria with a compound of any of Formulae I-VIII (which appearelsewhere herein) or a salt thereof.

The present invention is further directed to a process for inhibitingadherence of bacteria to a host cell, wherein the host cell is in a cellculture and the bacteria is treated by introducing a compound of any ofFormula I-VIII (which appear elsewhere herein) or a salt thereof to thecell culture.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, processes have been developedenabling the preparation of secondary and tertiary amino methylated2-pyridinones. These 2-pyridinones have been found to inhibit or evenprevent bacterial infection of host cells by interrupting the formationof pili. Thus, for example, these 2-pyridinones may be employed toinhibit biofilm formation and thereby inhibit adherence of the bacteriato a host cell; this may be accomplished when the composition interfereswith the function of chaperones required for the assembly of pili frompilus subunits in diverse Gram-negative bacteria. Such interference isparticularly effective since the formation of pili is essential tobacterial pathogenicity and since the production of the pilus subunitsin the absence of chaperones is known to be directly toxic.

1. Amino Methylated 2-Pyridinone Compositions

In general, the secondary or tertiary amino methylated 2-pyridinonescorrespond to Formula 1 or a salt thereof:

wherein

R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, heterocyclo, or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen;

R₄ and R₅ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or heterocyclo, provided at least one of R₄ and R₅ is otherthan hydrogen; and

the “Z” ring contains 5 to 7 ring atoms selected from the groupconsisting of carbon, oxygen, nitrogen and sulfur, provided (i) at least4 of the ring atoms are carbon when the “Z” ring contains 7 ring atoms,and (ii) at least 3 of the ring atoms are carbon when the “Z” ringcontains 5 or 6 ring atoms.

As previously noted, R₂ and R₃ are independently hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, or, in combination with thenitrogen atom to which they are bonded, form a heterocyclo, provided atleast one of R₂ and R₃ is other than hydrogen (i.e., at least one of R₂and R₃ is hydrocarbyl, substituted hydrocarbyl or heterocyclo). When oneand only one of R₂ and R₃ is hydrogen, the 2-pyridinone is characterizedherein as a secondary amino methylated 2-pyridinone. When neither of R₂and R₃ are hydrogen, the 2-pyridinone is characterized herein as atertiary amino methylated 2-pyridinone.

In one embodiment, the 2-pyridinone is a secondary amino methylated2-pyridinone and one of R₂ and R₃ is hydrocarbyl or substitutedhydrocarbyl. In this embodiment, for example, R₂ or R₃ may be alkyl,alkenyl, alkynyl, aryl, or a combination thereof such as alkaryl. Ingeneral, when R₂ or R₃ is alkyl, C1 to C6 alkyls are typicallypreferred. For example, R₂ or R₃ may be methyl, ethyl, propyl (straight,branched or cyclic), butyl (straight, branched or cyclic), pentyl,(straight, branched or cyclic), or hexyl (straight, branched or cyclic).Alternatively, R₂ or R₃ may be substituted alkyl, alkenyl, alkynyl,aryl, or a combination thereof such as substituted alkaryl. For example,R₂ or R₃ may be substituted methyl, substituted ethyl, substitutedpropyl (straight, branched or cyclic), substituted butyl (straight,branched or cyclic); substituted pentyl, (straight, branched or cyclic),or substituted hexyl (straight, branched or cyclic) wherein thesubstituent(s) is/are selected from the group consisting of heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties. In onesuch embodiment R₂ or R₃ may be heterocyclo or alkyl.

Alternatively, the 2-pyridinone may be a secondary amino methylated2-pyridinone and one of R₂ and R₃ is heterocyclo. In this embodiment,for example, R₂ or R₃ may be a 5 or 6-membered heterocycle which issaturated, partially unsaturated or fully unsaturated; in addition, thering atoms of the heterocycle may be further substituted. Exemplary 5and 6-membered heterocycles include furyl, thienyl, pyridyl, oxazolyl,isoxazolyl, pyrrolyl, indolyl, quinolinyl, and isoquinolinyl. In oneembodiment, for example, the heterocycle may be optionally substitutedindolyl, furyl, or pyrrolyl. If substituted, the 5 or 6-membered ringmay have one or more substituents selected from the group consisting ofheterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto,acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ethermoieties.

The 2-pyridinone may alternatively be a tertiary amino methylated2-pyridinone with R₂ and R₃ independently being selected fromhydrocarbyl, substituted hydrocarbyl, and heterocyclo. For example, oneof R₂ and R₃ may be hydrocarbyl or substituted hydrocarbyl when theother of R₂ and R₃ is heterocyclo. Similarly, one of R₂ and R₃ may behydrocarbyl when the other is substituted hydrocarbyl. In each of theseembodiments, R₂ and R₃, the hydrocarbyl, substituted hydrocarbyl, and/orheterocyclo groups may be any of the moieties previously described forR₂ or R₃ in the embodiment in which the 2-pyridinone is a secondaryamino methylated 2-pyridinone. For example, R₂ and/or R₃ may be alkyl,alkenyl, alkynyl, aryl, or a combination thereof such as alkaryl. Ingeneral, when R₂ and/or R₃ is alkyl, C1 to C6 alkyls are typicallypreferred. Thus, R₂ and/or R₃ may be methyl, ethyl, propyl (straight,branched or cyclic), butyl (straight, branched or cyclic), pentyl,(straight, branched or cyclic), or hexyl (straight, branched or cyclic).Alternatively, R₂ and/or R₃ may be substituted alkyl, alkenyl, alkynyl,aryl, or a combination thereof such as substituted alkaryl. For example,R₂ and/or R₃ may be substituted methyl, substituted ethyl, substitutedpropyl (straight, branched or cyclic), substituted butyl (straight,branched or cyclic), substituted pentyl, (straight, branched or cyclic),or substituted hexyl (straight, branched or cyclic) wherein thesubstituent(s) is/are selected from the group consisting of heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties. By way offurther example, R₂ and/or R₃ may be a 5 or 6-membered heterocycle whichis saturated, partially unsaturated or fully unsaturated. Exemplary 5and 6-membered heterocycles include furyl, thienyl, pyridyl, oxazolyl,isoxazolyl, pyrrolyl, indolyl, quinolinyl, and isoquinolinyl. In onesuch embodiment, the 5 or 6-membered ring is unsubstituted. In anotherembodiment, the 5 or 6-membered ring has one or more substituentsselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro, amino, amido, thiol,ketal, acetal, ester and ether moieties. In general, when R₂ and/or R₃is aryl monocyclic or bicyclic groups containing from 6 to 12 carbons inthe ring portion are typically preferred. Thus, R₂ and/or R₃ may bephenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl orsubstituted naphthyl.

In a further embodiment, the 2-pyridinone is a tertiary amino methylated2-pyridinone with R₂, R₃ and the nitrogen atom to which they are eachbonded defining a nitrogen-containing heterocyclo. In this embodiment,for example, R₂, R₃ and the nitrogen atom to which they are each bondeddefine a 5- or 6-membered nitrogen-containing ring such as substitutedmorpholine, piperidine, or 2- or 4-pyrolidine. Optionally, theheterocyclo ring is substituted by one or more substituents selectedfrom the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties

In a further embodiment of the amino methylated 2-pyridinone, (i) R₂ andR₃ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl orheterocyclo, provided at least one of R₂ and R₃ is other than hydrogenand (ii) each X₁₁, when present, is an electron pair, hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, or oxo.

In general, R₄ and R₅ are independently hydrogen, hydrocarbyl,substituted hydrocarbyl, or heterocyclo, provided at least one of R₄ andR₅ is other than hydrogen (i.e., at least one of R₄ and R₅ ishydrocarbyl, substituted hydrocarbyl or heterocyclo). For example, R₄may be hydrocarbyl, substituted hydrocarbyl or heterocyclo when R₅ ishydrogen. Alternatively, R₅ may be hydrocarbyl, substituted hydrocarbylor heterocyclo when R₄ is hydrogen. In another embodiment, each of R₄and R₅ are selected independently from hydrocarbyl, substitutedhydrocarbyl and heterocyclo. That is, one of R₄ and R₅ may behydrocarbyl or substituted hydrocarbyl when the other of R₄ and R₅ isheterocyclo. Similarly, one of R₄ and R₅ may be hydrocarbyl when theother is substituted hydrocarbyl. In each of these embodiments, thehydrocarbyl, substituted hydrocarbyl, and/or heterocyclo groups may beany of the moieties previously described for R₂ and R₃. In one presentlypreferred embodiment, each of R₄ and R₅ is hydrocarbyl. For example, oneof R₄ and R₅ may be aryl (e.g., phenyl or naphthyl) when the other isalkyl. In general, when R₄ and/or R₅ is alkyl, C3 to C15 alkyls aretypically preferred. For example, when R₄ and/or R₅ is alkyl, one orboth substituents may be methyl, ethyl, propyl, isopropyl, butyl, hexyl,octyl, nonyl, undecyl, dodecyl and the like. Alternatively, one of R₄and R₅ may be phenyl when the other is naphthyl.

As depicted in Formula 1, the “Z” ring, together with the “Y” ring formsa fused, bicyclic ring system. As depicted, the “Y” ring contains sixring atoms with one of the ring atoms being nitrogen. As previouslydefined, the “Z” ring contains 5 to 7 ring atoms, with two of these 5 to7 ring atoms (i.e., one nitrogen and one carbon atom) also being part ofthe “Y” ring. The remaining atoms of the “Z” ring are selected from thegroup consisting of carbon, oxygen, nitrogen, and sulfur, provided,however, when the “Z” ring is a 6 or 7-membered ring, no more than threering atoms of the “Z” ring are oxygen, nitrogen, or sulfur, or acombination thereof and when the “Z” ring is a 5-membered ring, no morethan two ring atoms of the “Z” ring are oxygen, nitrogen, or sulfur, ora combination thereof. Stated another way, when the “Z” ring is a 6 or7-membered ring, in addition to the nitrogen atom which is shared by theX and Y rings, two additional ring atoms in the “Z” ring may be selectedfrom oxygen, nitrogen and sulfur and when the “Z” ring is a 5-memberedring, in addition to the nitrogen atom which is shared by the X and Yrings, one additional ring atom in the “Z” ring may be selected fromoxygen, nitrogen and sulfur.

In one such embodiment, the “Z” ring is a 5, 6 or 7-membered saturatedor partially unsaturated ring. For example, in this embodiment thecompound may correspond to Formula II:

wherein

R₂, R₃, R₄, and R₅ are as defined in connection with Formula I and eachof the permutations thereof;

X₁ is a bond, carbon, oxygen, nitrogen, or sulfur;

X₂ is a bond, carbon, oxygen, nitrogen, or sulfur;

X₃ and X₄ are independently carbon, oxygen, nitrogen, or sulfur;

X₅ is carbon or nitrogen;

each X₁₁, when present, is an electron pair, hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, oxo, halo, or acyl;

each X₂₂, when present, is an electron pair, hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, or oxo;

each X₃₃ and X₄₄ is independently an electron pair, hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, or oxo;

X₅₅ is —CH₂OX₅₅₅, —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅, —CHO, —B(OH)₂,or —PO(OH)₂; and

X₅₅₅ is hydrogen or other cation, hydrocarbyl, substituted hydrocarbyl,or heterocyclo;

provided, however, (i) X₁₁, or X₂₂ is not present when X₁, or X₂,respectively, is a bond; (ii) no more than two of X₁, X₂, X₃, X₄ and X₅are oxygen, nitrogen or sulfur when the “Z” ring contains 6 or 7 ringatoms, and (iii) no more than one of X₁, X₂, X₃, X₄ and X₅ are oxygen,nitrogen or sulfur when the “Z” ring contains 5 ring atoms.

In this embodiment, R₂, R₃, R₄, and R₅ may be present in each of thepermutations previously described in connection with Formula I. Forexample, the compound corresponding to Formula II, or salt thereof, maybe a secondary amino methylated 2-pyridinone (wherein one, but only oneof R₂ and R₃ is hydrogen); in this embodiment, one of R₂ and R₃ ishydrocarbyl, substituted hydrocarbyl or heterocyclo with thehydrocarbyl, substituted hydrocarbyl or heterocyclo being as describedin connection with Formula I. Alternatively, the compound correspondingto Formula II, or salt thereof, may be a tertiary amino methylated2-pyridinone (wherein neither R₂ or R₃ is hydrogen); in this embodiment,each of R₂ and R₃ are independently hydrocarbyl, substituted hydrocarbylor heterocyclo with the hydrocarbyl, substituted hydrocarbyl orheterocyclo moieties and each of the possible permutations thereof beingas described in connection with Formula I.

As depicted, the “Z” ring, i.e., the ring defined by X₁-X₅ and thecarbon and nitrogen atoms to which X₁ and X₅, respectively, are bonded,may be a five, six or seven-membered ring. When the “Z” ring is aseven-membered ring, neither X₁ nor X₂ is a bond. When the “Z” ring is asix-membered ring, however, X₁ is a bond directly linking X₂ to thecarbon atom of the other ring of the fused bicyclic system (i.e., thering designated as the “Y” ring in Formula I). When the “Z” ring is afive-membered ring, X₁ and X₂, in combination, define a bond directlylinking X₃ to the carbon atom of the other ring of the fused bicyclicsystem (i.e., the ring designated as the “Y” ring in Formula I). Whenthe “Z” ring is a six-membered ring, therefore, neither X₁₁ is presentsince the ring atom to which each X₁₁ is shown as being a substituent isnot present. Similarly, when the “Z” ring is a five-membered ring,neither of the X₁₁ substituents nor either of the X₁₂ substituents ispresent since the ring atoms to which they are shown as being attachedare not present.

As depicted in Formula II, X₁-X₅ are substituted by two X₁₁-X₅₅substituents, respectively. As defined, each X₁₁-X₅₅ may be an electronpair; for example, one or more of X₁₁-X₅₅ may be an electron pair whentwo or more of X₁-X₅ are not fully saturated, e.g., an Sp² hybridizedcarbon. Alternatively, one or more of X₁₁-X₅₅ may be an electron pairwhen one of X₁-X₅ is oxygen, sulfur or nitrogen. Thus, for example, oneof X₁-X₅ may be a saturated nitrogen atom bonded to two other ring atomsand a corresponding substituent designated X₁₁-X₅₅ (depending upon thering position of nitrogen atom) with the other corresponding substituentdesignated X₁₁-X₅₅ being an electron pair of the nitrogen atom. Also, itis contemplated that a sulfur or ring nitrogen atom may be in any oftheir available oxidation states. For example, a ring sulfur atom may bein sulfide oxidation state (—S—), the sulfoxide oxidation state (—SO—),or the sulfone oxidation state (—SO₂—). Similarly, a ring nitrogen atommay be in its N-oxide oxidation state (—N(═O)—). For example, if X₁ issulfur, each X₁₁ may be an electron pair (which corresponds to thesulfide oxidation state), one X₁₁ may be an electron pair when the otheris oxo (which corresponds to sulfoxide oxidation state) or each X₁₁ maybe oxo (which corresponds to the sulfone oxidation state).

In one embodiment, X₅₅ is an acyl or acyl-containing moiety. Forexample, in this embodiment X₅₅ may be —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅,—CO₂X₅₅₅, or —CHO. In a further embodiment, X₅₅ may be —CH(CO₂X₅₅₅)₂. Ingeneral, X₅₅₅ is preferably hydrogen or another cation such as an alkalimetal, an alkaline earth metal or ammonium in this embodiment. Inanother embodiment, X₅₅ may be —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, or —CO₂X₅₅₅.In another embodiment, X₅₅ may be —CH(CO₂X₅₅₅)₂ or —CH₂CO₂X₅₅₅. In stillanother embodiment, X₅₅ may be —CH(CO₂X₅₅₅)₂. In a further embodiment,X₅₅ is —B(OH)₂, —PO(OH)₂, or tetrazole.

While the “Z” ring may be seven-membered in one embodiment, it ispresently preferred that the “Z” ring be a five or six-membered ring. Inthis embodiment, the secondary or tertiary amino methylated 2-pyridinonecorresponds to Formula III:

wherein R₂, R₃, R₄, R₅, X₂, X₃, X₄, X₅, X₂₂, X₃₃, X₄₄, and X₅₅ are asdescribed in connection with Formula II and each of the permutationsthereof. In one embodiment, X₃₃ and X₄₄ is independently an electronpair, hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, oxo,halo or acyl.

Still more preferably, the “Z” ring is a 5-membered ring. For example,in this embodiment, the secondary or tertiary amino methylated2-pyridinone compound corresponds to Formula IV:

wherein R₂, R₃, R₄, R₅, X₃, 4, X₅, X₃₃, X₄₄, and X₅₅ are as described inconnection with Formula II and each of the permutations thereof. In oneembodiment, each X₄₄ is independently an electron pair, hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, oxo, halo or acyl.

When the secondary or tertiary amino methylated 2-pyridinone compoundcorresponds to Formula IV and X₄ is carbon, a chiral center may exist atthe ring position occupied by X₅. Thus, for example, isomerscorresponding to Formula Va and Vb may exist:

wherein R₂, R₃, R₄, R₅, X₃, X₅, X₃₃, X₄₄, and X₅₅ are as described inconnection with Formula II and each of the permutations thereof. In oneembodiment, the secondary or tertiary amino methylated 2-pyridinonecompound corresponds to Formula Va. In another embodiment, the secondaryor tertiary amino methylated 2-pyridinone compound corresponds toFormula Vb. In another embodiment, each X₄₄ is hydrogen, hydrocarbyl,halo or acyl.

In one preferred embodiment of the present invention, the “Z” ring is a5-membered ring containing a sulfur atom. For example, in thisembodiment, the compound may correspond to Formula VIa or VIb:

wherein R₂, R₃, R₄, R₅, X₅, X₃₃, X₄₄, and X₅₅ are as described inconnection with Formula II and each of the permutations thereof.

In one embodiment in which the secondary or tertiary amino methylated2-pyridinone corresponds to Formula VI, sulfur is in the sulfideoxidation state (i.e., each X₃₃ is an electron pair). In another suchembodiment, sulfur is in the sulfoxide oxidation state (i.e., one X₃₃ isan electron pair and the other is oxo (═O)). In yet another suchembodiment, sulfur is in the sulfone oxidation state (i.e., each X₃₃ isoxo (═O)). In yet another embodiment, X₄₄ is hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, oxo, halo or acyl. In stillanother embodiment, X₄₄ is hydrogen, alkyl, halo, —C(O)R₄₄ or—C(O)N(R₄₄)₂ and each R₄₄ is independently hydrogen, alkyl or aryl. Inanother embodiment, X₅₅ is —CO₂X₅₅₅. In yet another embodiment, X₅₅₅ maybe hydrogen, alkyl, or an alkaline metal. In still another embodiment,(i) R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl or heterocyclo, and (ii) X₄₄ is hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, or oxo. In yet another embodiment,R₂ is alkyl. In anther embodiment, R₂ and R₃, in combination with thenitrogen atom to which they are bonded from a heterocyclo. In anotherembodiment, R₄ is alkyl or aryl. In another embodiment, R₅ is alkyl.

When the secondary or tertiary amino methylated 2-pyridinone correspondsto Formula VI, X₄₄ may have any of the values previously described forX₄₄. Typically, however, X₄₄ will be hydrogen or hydrocarbyl. Moretypically, X₄₄ will be hydrogen.

In one preferred embodiment of the present invention, the “Z” ring is asaturated 5-membered ring. For example, in this embodiment, the compoundmay correspond to Formula VIIa or VIIb:

wherein R₂, R₃, R₄, R₅, X₃₃, and X₅₅ are as described in connection withFormula II and each of the permutations thereof.

When the secondary or tertiary amino methylated 2-pyridinone correspondsto Formula VIIa or VIIb, the sulfur atom may be in the sulfide oxidationstate (i.e., each X₃₃ is an electron pair). Alternatively, the sulfuratom may be in the sulfoxide oxidation state (i.e., one X₃₃ is anelectron pair and the other is oxo (═O)). The sulfur atom may also be inthe sulfone oxidation state (i.e., each X₃₃ is oxo (═O)).

In one embodiment, the 2-pyridinone corresponds to Formula VIIa or VIIb,one of R₂ and R₃ is hydrogen and the other is hydrocarbyl or substitutedhydrocarbyl. In this embodiment, for example, one of R₂ or R₃ ishydrogen and the other is alkyl, alkenyl, alkynyl, aryl, or acombination thereof such as alkaryl. For example, R₂ or R₃ may beoptionally substituted methyl, ethyl, propyl (straight, branched orcyclic), butyl (straight, branched or cyclic), pentyl, (straight,branched or cyclic), or hexyl (straight, branched or cyclic) wherein thesubstituent(s) is/are selected from the group consisting of heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties. In onesuch embodiment R₂ or R₃ may be heterocyclo or alkyl.

Alternatively, the 2-pyridinone may correspond to Formula VIIa or VIIbwherein one of R₂ and R₃ is hydrogen and the other is heterocyclo. Inthis embodiment, for example, R₂ or R₃ may be optionally substitutedfuryl, thienyl, pyridyl, oxazolyl, isoxazolyl, pyrrolyl, indolyl,quinolinyl, and isoquinolinyl. In one particular embodiment, forexample, the heterocycle may be optionally substituted indolyl, furyl,or pyrrolyl. If substituted, the 5 or 6-membered ring may have one ormore substituents selected from the group consisting of heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties.

The 2-pyridinone may alternatively correspond to Formula VIIa or VIIbwherein each of R₂ and R₃ are independently selected from hydrocarbyl,substituted hydrocarbyl, and heterocyclo. For example, one of R₂ and R₃may be hydrocarbyl or substituted hydrocarbyl when the other of R₂ andR₃ is heterocyclo. Similarly, one of R₂ and R₃ may be hydrocarbyl whenthe other is substituted hydrocarbyl. In each of these embodiments, theR₂ and R₃ hydrocarbyl, substituted hydrocarbyl, and/or heterocyclogroups may be any of the moieties previously described for R₂ or R₃ inconnection with Formulae VIIa and VIIb, and the various permutationsthereof. For example, R₂ and/or R₃ may be alkyl, alkenyl, alkynyl, aryl,or a combination thereof such as alkaryl. In general, when R₂ and/or R₃is alkyl, C1 to C6 alkyls are typically preferred. Thus, R₂ and/or R₃may be methyl, ethyl, propyl (straight, branched or cyclic), butyl(straight, branched or cyclic), pentyl, (straight, branched or cyclic),or hexyl (straight, branched or cyclic). Alternatively, R₂ and/or R₃ maybe substituted alkyl, alkenyl, alkynyl, aryl, or a combination thereofsuch as substituted alkaryl. For example, R₂ and/or R₃ may besubstituted methyl, substituted ethyl, substituted propyl (straight,branched or cyclic), substituted butyl (straight, branched or cyclic),substituted pentyl, (straight, branched or cyclic), or substituted hexyl(straight, branched or cyclic) wherein the substituent(s) is/areselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro, amino, amido, thiol,ketal, acetal, ester and ether moieties. By way of further example, R₂and/or R₃ may be a 5 or 6-membered heterocycle which is saturated,partially unsaturated or fully unsaturated. Exemplary 5 and 6-memberedheterocycles include furyl, thienyl, pyridyl, oxazolyl, isoxazolyl,pyrrolyl, indolyl, quinolinyl, and isoquinolinyl, In one suchembodiment, the 5 or 6-membered ring is unsubstituted. In anotherembodiment, the 5 or 6-membered ring has one or more substituentsselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, keto, acyloxy, nitro, amino, amido, thiol,ketal, acetal, ester and ether moieties. By way of further example, oneof R₂ and/or R₃ may be optionally substituted aryl when the other ishydrocarbyl, substituted hydrocarbyl or heterocyclo wherein thehydrocarbyl, substituted hydrocarbyl or heterocyclo moieties may be aspreviously described in connection with R₂ and/or R₃.

In a further embodiment, the 2-pyridinone is a tertiary amino methylated2-pyridinone with R₂, R₃ and the nitrogen atom to which they are eachbonded defining a nitrogen-containing heterocyclo. In this embodiment,for example, R₂, R₃ and the nitrogen atom to which they are each bondeddefine a 5- or 6-membered nitrogen-containing ring such as morpholino,pyrrolyl, or pipridine. Optionally, the heterocyclo ring is substitutedby one or more substituents selected from the group consisting ofheterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto,acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ethermoieties.

In general, R₄ and R₅ are independently hydrogen, hydrocarbyl,substituted hydrocarbyl, or heterocyclo, provided at least one of R₄ andR₅ is other than hydrogen (i.e., at least one of R₄ and R₅ ishydrocarbyl, substituted hydrocarbyl or heterocyclo). For example, R₄may be hydrocarbyl, substituted hydrocarbyl or heterocyclo when R₅ ishydrogen. Alternatively, R₅ may be hydrocarbyl, substituted hydrocarbylor heterocyclo when R₄ is hydrogen. In another embodiment, each of R₄and R₅ are selected independently from hydrocarbyl, substitutedhydrocarbyl and heterocyclo. That is, one of R₄ and R₅ may behydrocarbyl or substituted hydrocarbyl when the other of R₄ and R₅ isheterocyclo. Similarly, one of R₄ and R₅ may be hydrocarbyl when theother is substituted hydrocarbyl. In each of these embodiments, thehydrocarbyl, substituted hydrocarbyl, and/or heterocyclo groups may beany of the moieties previously described for R₂ and R₃. In one presentlypreferred embodiment, each of R₄ and R₅ is hydrocarbyl. For example, oneof R₄ and R₅ may be aryl (e.g., phenyl or naphthyl) when the other isalkyl. In general, when R₄ and/or R₅ is alkyl, C3 to C15 alkyls aretypically preferred. Alternatively, one of R₄ and R₅ may be phenyl whenthe other is naphthyl.

In another preferred embodiment of the present invention, the “Z” ringis a saturated 5-membered ring. For example, in this embodiment, thecompound may correspond to Formula VIIIa or VIIIb:

wherein R₂, R₃, R₄, R₅, and X₅₅ are as described in connection withFormula II and each of the permutations thereof.

The compounds corresponding to Formulae I-VIII and the salts thereof mayhave one or more asymmetric carbons and thus, the compositions may existin diastereomeric, racemic or optically active forms. All of thesestereoisomers are contemplated within the scope of the presentinvention. More particularly, the present invention includes theenantiomers, diastereomers, racemic mixtures and other mixtures thereof.

The compounds corresponding to Formula I-VIII may be in the form of freebases or pharmaceutically acceptable acid addition salts or other saltsthereof. The term “pharmaceutically-acceptable salts” embraces saltscommonly used to form alkali metal salts and to form addition salts offree acids or free bases. The nature of the salt may vary, provided thatit is pharmaceutically-acceptable. Suitable pharmaceutically-acceptableacid addition salts of compounds for use in the present methods may beprepared from an inorganic acid or from an organic acid. Examples ofsuch inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which are formic, acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, P-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of use in the present methods includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound by reacting, for example, the appropriate acid or base with thecompound of any Formula set forth herein.

2. Synthetic Processes

In general, tertiary amino methylated 2-pyridinones may be prepared viathe Mannich reaction using the corresponding 2-pyridinone and an iminiumsalt according to the following reaction scheme:2-pyridinone+H₂C═R₃₀ ⁺X⁻→aminomethylated 2-pyridinone

wherein the amino methylated 2-pyridinone corresponds to any of FormulaeI-VIII described above, R₃₀ ⁺ is a disubstituted quaternary nitrogenatom, X⁻ is a halide and the 2-pyridinone corresponds to any of FormulaeI-VIII described above, except that the 2-pyridinone lacks theaminomethyl substituent. Thus, for example, in one embodiment thetertiary amino methylated 2-pyridinone corresponding to Formula I may beprepared according to the following reaction scheme:

wherein R₂, R₃, R₄, and R₅ are as defined in connection with Formula I,X⁻ is a halide, preferably chloride or iodide, and R₃₀ ⁺ is adisubstituted quaternary nitrogen atom with the substituents of thenitrogen atom corresponding to R₂ and R₃. Alternatively, therefore, theiminium salt may be represented by the formula H₂C═N(R₂)(R₃)⁺X⁻ whereinX⁻ is a halide, and R₂ and R₃ are as previously defined. Thus, in oneembodiment, R₂ and R₃ may each be alkyl; for example, R₂ and R₃ may eachbe methyl, ethyl and the like. Alternatively, R₂ and R₃ may, incombination with the ammonium nitrogen atom to which they are attached,define a nitrogen-containing 5 or 6-membered ring such as morpholino,pyrrolyl, or pipridine.

In general, the reaction may be carried out over a range of temperaturesand in a range of solvents in which the reactants are soluble. Exemplarysolvents include acetonitrile, toluene, N-methyl-2-pyrrolidinone,dimethylformamide, dichloroethane and dichloromethane. Typically, thereaction will be carried out at a temperature in excess of 60° C.,preferably at a temperature in excess of 100° C.

To potentially reduce reaction times and/or increase yields, thereaction mixture may be irradiated with microwaves. In general, themicrowaves preferably have a wavelength of 1 mm-1 m corresponding and apower of 0.3-300 Ghz. Typically, the microwaves have a wavelength of12.2 cm and a power of 2.45 Ghz. The reaction mixture may be irradiatedfor a period from seconds to minutes, with irradiation times typicallybeing in the range of about four minutes to about fourteen minutes.During irradiation, the reaction mixture is preferably maintained at atemperature of about 80° C. to about 180° C., more preferably about 130°C. to about 150° C.

Secondary amino methylated 2-pyridinone may be prepared in a somewhatsimilar manner, except that a halogenated iminium salt is substitutedfor the iminium salt in the first reaction step. This produces a formylsubstituted pyridinone which can be reductively aminated using areducing agent and an amine according to the following reaction scheme:

wherein the amino methylated 2-pyridinone corresponds to any of FormulaeI-VIII described above, R₃₀ ⁺ is a disubstituted quaternary nitrogenatom, X is halogen and the 2-pyridinone corresponds to any of FormulaeI-VIII described above, except that the 2-pyridinone lacks theaminomethyl substituent. Thus, for example, in one embodiment thetertiary amino methylated 2-pyridinone corresponding to Formula I may beprepared according to the following reaction scheme:

wherein R₂, R₃, R₄, and R₅ are as defined in connection with Formula I,X is halogen, preferably chloride or iodine, R₃₀ ⁺ is a quaternarynitrogen atom, and the amine is a secondary amine represented by theformula NHR₂R₃, wherein R₂ and R₃ are as described above. Thus, in oneembodiment, R₂ and R₃ may each be alkyl; for example, R₂ and R₃ may eachbe methyl, ethyl and the like. Alternatively, R₂ and R₃ may, incombination with the ammonium nitrogen atom to which they are attached,define a nitrogen-containing 5 or 6-membered ring such as morpholino,pyrrolyl, or pipridine.

In general, the reducing agent may be any conventional reducing agent,provided the reducing agent does not undesirably reduce othersubstituents in the molecule. Preferably a nucleophilic reducing agentis used. For example, under appropriate conditions the reducing agentmay be H₂ gas and an organometalic. In general, borohydrides such assodium borohydrides or sodium 3-acetoxy borohydride are preferred.Alternatively, a borohydride such as sodium cyanoborohydride may beused.

The reaction may be carried out over a range of temperatures and in arange of solvents in which the reactants are soluble. Exemplary solventsinclude acetonitrile, toluene, N-methyl-2-pyrrolidinone,dimethylformamide, and dichloroethane. Typically, the reaction will becarried out at a temperature in excess of 0° C., preferably at atemperature in excess of 20° C.

3. Uses

Compounds corresponding to any of Formulae I-VIII and the salts thereofmay be used in vitro or in vivo to inhibit pili formation by bacteria.Thus, for example, a compound of the present invention or a salt thereofmay be introduced to a cell culture to inhibit pili formation.Alternatively, a compound of the present invention or a salt thereof maybe administered to a mammal to inhibit pili formation in vivo. In afurther alternative, a prosthetic implant may be coated with a compoundof the present invention or salt thereof before the prosthesis isimplanted in a patient's body.

For in vivo applications, a pharmaceutical composition comprising aneffective amount of a compound of the present invention (or saltthereof) in combination with at least one pharmaceutically orpharmacologically acceptable carrier is administered to an animal,including humans. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of thecompounds. The carrier is “pharmaceutically or pharmacologicallyacceptable” if it does not produce an adverse, allergic or otheruntoward reaction when administered to a mammal or human, asappropriate.

The pharmaceutical compositions containing the compounds (or salts) ofthe present invention may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the invention can be formulated for any route ofadministration so long as the target tissue is available via that route.Suitable routes of administration include, but are not limited to, oral,parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal), topical (nasal, transdermal,intraocular), intravesical, intrathecal, enteral, pulmonary,intralymphatic, intracavital, vaginal, transurethral, intradermal,aural, intramammary, buccal, orthotopic, intratracheal, intralesional,percutaneous, endoscopical, transmucosal, sublingual and intestinaladministration.

Pharmaceutically acceptable carriers for use in the compositions of thepresent invention are well known to those of ordinary skill in the artand are selected based upon a number of factors: the particular compoundused, and its concentration, stability and intended bioavailability; thedisease, disorder or condition being treated with the composition; thesubject, its age, size and general condition; and the route ofadministration. Suitable carriers are readily determined by one ofordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp. 1492-1517, the contents of which areincorporated herein by reference).

The compositions are preferably formulated as tablets, dispersiblepowders, pills, capsules, gelcaps, caplets, gels, liposomes, granules,solutions, suspensions, emulsions, syrups, elixirs, troches, dragees,lozenges, or any other dosage form which can be administered orally.Techniques and compositions for making oral dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosaqe Forms 2nd Edition (1976).

The compositions of the invention for oral administration comprise aneffective amount of a compound of the invention in a pharmaceuticallyacceptable carrier. Suitable carriers for solid dosage forms includesugars, starches, and other conventional substances including lactose,talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol,sorbitol, calcium phosphate, calcium carbonate, sodium carbonate,kaolin, alginic acid, acacia, corn starch, potato starch, sodiumsaccharin, magnesium carbonate, tragacanth, microcrystalline cellulose,colloidal silicon dioxide, croscarmellose sodium, talc, magnesiumstearate, and stearic acid. Further, such solid dosage forms may beuncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

The compounds and salts of the present invention may also be formulatedfor parenteral administration, e.g., formulated for injection viaintravenous, intraarterial, subcutaneous, rectal, subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective amount ofthe composition in a pharmaceutically acceptable carrier. Dosage formssuitable for parenteral administration include solutions, suspensions,dispersions, emulsions or any other dosage form which can beadministered parenterally. Techniques and compositions for makingparenteral dosage forms are known in the art.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N—(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide-amides,2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone);esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esterssuch as monoacetin, diacetin, and triacetin, aliphatic or aromaticesters such as ethyl caprylate or octanoate, alkyl oleate, benzylbenzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerinsuch as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate,ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acidesters of sorbitan, fatty acid derived PEG esters, glycerylmonostearate, glyceride esters such as mono, di, or tri-glycerides,fatty acid esters such as isopropyl myristrate, fatty acid derived PEGesters such as PEG-hydroxyoleate and PEG-hydroxystearate,N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleicpolyesters such as poly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄,poly(oxyethylene)₁₅₋₂₀ monooleate, poly(oxyethylene)₁₅₋₂₀ mono12-hydroxystearate, and poly(oxyethylene)₁₅₋₂₀ mono ricinoleate,polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitanmonooleate, polyoxyethylene-sorbitan monopalmitate,polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitanmonostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas,Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acidesters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylatedcastor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution),saccharide fatty acid esters (i.e., the condensation product of amonosaccharide (e.g., pentoses such as ribose, ribulose, arabinose,xylose, lyxose and xylulose, hexoses such as glucose, fructose,galactose, mannose and sorbose, trioses, tetroses, heptoses, andoctoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose)or oligosaccharide or mixture thereof with a C₄-C₂₂ fatty acid(s)(e.g.,saturated fatty acids such as caprylic acid, capric acid, lauric acid,myristic acid, palmitic acid and stearic acid, and unsaturated fattyacids such as palmitoleic acid, oleic acid, elaidic acid, erucic acidand linoleic acid), or steroidal esters); alkyl, aryl, or cyclic ethershaving 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethylisosorbide, diethylene glycol monoethyl ether); glycofurol(tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutylketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes,hexane, n-decane, n-dodecane, hexane, sulfolane, tetramethylenesulfon,tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), ortetramethylenesulfoxide); oils of mineral, vegetable, animal, essentialor synthetic origin (e.g., mineral oils such as aliphatic or wax-basedhydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic basedhydrocarbons, and refined paraffin oil, vegetable oils such as linseed,tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed,coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil andglycerides such as mono-, di- or triglycerides, animal oils such asfish, marine, sperm, cod-liver, haliver, squalene, squalane, and sharkliver oil, oleic oils, and polyoxyethylated castor oil); alkyl or arylhalides having 1-30 carbon atoms and optionally more than one halogensubstituent; methylene chloride; monoethanolamine; petroleum benzin;trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenicacid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoicacid); polyglycol ester of 12-hydroxystearic acid and polyethyleneglycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany);polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitanmonooleate.

Other pharmaceutically acceptable solvents for use in the invention arewell known to those of ordinary skill in the art, and are identified inThe Chemotherapy Source Book (Williams & Wilkens Publishing), TheHandbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al.,eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Reminqton'sPharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing,Easton, Pa., 1995), The United States Pharmacopeia 24, The NationalFormulary 19, (National Publishing, Philadelphia, Pa., 2000), A. J.Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products,JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).

Definitions

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The “heterosubstituted methyl” moieties described herein are methylgroups in which the carbon atom is covalently bonded to at least oneheteroatom and optionally with hydrogen, the heteroatom being, forexample, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, orhalogen atom. The heteroatom may, in turn, be substituted with otheratoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol,ketals, acetals, esters or ether moiety.

The “heterosubstituted acetate” moieties described herein are acetategroups in which the carbon of the methyl group is covalently bonded toat least one heteroatom and optionally with hydrogen, the heteroatombeing, for example, a nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or halogen atom. The heteroatom may, in turn, be substitutedwith other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido,thiol, ketals, acetals, esters or ether moiety.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

The term “heteroaromatic” as used herein alone or as part of anothergroup denote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may bebonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R isR¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo, and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing the scope ofthe invention defined in the appended claims. Furthermore, it should beappreciated that all examples in the present disclosure are provided asnon-limiting examples.

The following examples illustrate the invention.

EXAMPLES

The following non-limiting examples are provided to further illustratethe present invention. It should be appreciated by those of skill in theart that the techniques disclosed in the examples that follow representapproaches the inventors have found function well in the practice of theinvention, and thus can be considered to constitute examples of modesfor its practice. However, those of skill in the art should, in light ofthe present disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention.

Example 1

Microwave Assisted Synthesis of Highly Substituted Optically ActiveAminomethylated 2-Pyridones

In order to obtain the nitriles as amine precursors, brominated2-pyridones 5a-c were prepared in excellent yields (Scheme 1) usingbromine in AcOH.²³ Various cyanodehalogenation procedures employingtransition metal catalysts, e.g. palladium catalyzed reactions utilizingzinc cyanide as the cyanide source have worked well with arylhalides.^(24,25) Unfortunately, the brominated 2-pyridone 5a was notconsumed in these reactions, a fact that might be due to poisoning ofthe catalyst by the sulfur containing starting material. As aconsequence, the attention was turned to the original Rosenmund vonBraun cyanation employing CuCN in refluxing DMF and this time thedesired cyanosubstituted 2-pyridones were obtained. Still, the longreaction times and the rather harsh work up procedure were not idealresulting in low and irreproducible yields. Recent reports ofalternative cyanodehalogenation reactions performed on aryl halides haveshown that microwave assisted organic synthesis, MAOS, can improve thisreaction significantly.²⁵⁻²⁸ Therefore, it was investigated if thistechnology would be beneficial also for the Rosenmund Von Brauncyanodehalogenation. In the first attempts, 2-pyridone 5a and CuCN weredissolved in DMF and heated to 200° C. for 10 minutes in a microwaveapparatus. Although product was formed, the yields were still low (<30%)and a lot of unconsumed starting material was left. Extending thereaction time to 20 minutes gave more product but also significantamounts of byproducts were formed. Fortunately by increasing thetemperature to 220° C. and switching the solvent toN-methyl-2-pyrrolidinone, NMP, the cyano substituted 2-pyridone 6a wasobtained without detecting any competing side reaction. However, theisolated yields did not reflect the encouraging TLC and LCMS data. Thecommonly applied work up procedures for the Rosenmund von Braun reactionare often harsh, e.g. heating with HCl and FeCl₃,¹⁷ which clearlyaffected the total yield and was also a concern regarding the risk ofracemisation. Therefore, after trying different extraction procedureswith unsatisfactory outcomes, most of the solvent NMP was lyophilizedfrom water. This was followed by thorough extraction of the remainingsolid with CH₂Cl₂, which proved critical to obtain good overall yields.Final purification with column chromatography resulted incyano-substituted 2-pyridones 6a-c (Scheme 1) in very good yields takinginto account the presence of the sterically demanding naphtylsubstituent in 5a and 5b.

The remaining step to the desired primary amines was the reduction ofthe nitrile. To accomplish this transformation one had to take intoaccount some constrains. First, sulfur-assisted NaBH₄ reduction ofcarboxylic acid esters has been reported²⁹ indicating that one mightexperience selectivity problems and over reduction to the correspondingalcohol. Secondly, Padwa and co workers have shown that transition metalcatalyzed hydrogenation reactions at high pressure (90 psi) saturatesthe 2-pyridone skeleton.²³ Encouraged by a previous good experience inusing PdO in a selective dehalogenation of iodopyridone 5d atatmospheric pressure, hydrogenation was utilized in the initial attemptsto reduce the nitrile. Unfortunately, hydrogenations at atmosphericpressure using various catalysts e.g. PdO, Pd/C³⁰ and PtO₂ ³¹ as well asdifferent sources of hydrogen (hydrogen gas or ammonium formate) orelevated pressure at 50 psi all proved unsuccessful. Pd—S/C³² and Rh/C³³were also applied to investigate whether the low reactivity could beexplained by the aforementioned problem with poisoning of the catalyst,but without success. Now several electrophilic reducing agents that hadbeen reported as suitable reducing agents for nitrites such asN-Ethyl-N-isopropylaniline-borane (BACH-EI™),^(34,35) AlH₃.NMe₂Et³⁷ andBH₃.Me₂S (BMS)³⁸ were tested. Again, the cyano group remained intactusing both BACH-EI™ and AlH₃NMe₂Et, yet in the latter case the methylester was reduced to the corresponding alcohol according to LC-MS. Themost promising result was achieved with the BMS complex in THF, wheretraces of the desired amine could be detected after several hours atroom temperature. Refluxing overnight gave a substantial increase ofproduct formation albeit this also yielded considerable amounts ofbyproducts. With the intention to improve the unsatisfactory yields andreaction times, microwave irradiation was studied as an alternativesource of heating. Delightfully, this gave complete conversion of thehitherto almost inert cyano functionality in 60 seconds at 100° C. andprimary amines 7a-c were obtained in good yields (Scheme 1). The opticalpurity, however, continued to deteriorate also during thistransformation and the enantiomeric excess for primary amine 7b was only8%.

To introduce symmetrical dialkylamines the renowned Mannich reaction wasemployed, a classical method known since the early 1900's,³⁹ oftenmentioned as one of the most important C—C bond forming reactions inorganic chemistry.⁴⁰ Initial efforts using aqeous formaldehyde andprotic solvents proved unfruitful as no aminomethylated product could bedetected. However, switching to paraformaldehyde and dried aproticsolvents gave some product, still the yields were poor and a lot ofunidentified byproducts were formed. These well known limitations of theMannich reaction could possibly be diminished by shortening the reactiontimes and encouraged by the results from both the cyanodehalogenationand the borane dimethyl sulfide reduction of the nitrites, microwaveirradiation was applied also in this reaction. Disappointingly, initialstudies resulted in poor yields, at the best 28%. This could be due toslow formation of the in situ generated iminium salt, allowing competingside reactions to occur. To avoid these problems preformed methyleneiminium salts were used, giving a higher concentration of the reactivespecies. Thus, commercially available Eschenmoser's salt (I⁻Me₂N⁺=CH₂)and pyridone 4c were irradiated for 9 minutes in 1,2-dichloroethane at160° C. This improved the result substantially as 8a could be isolatedin 78% yield. The use of preformed iminiumsalts is a well provenstrategy in the Mannich reaction often known to shorten reaction timesand increase yields.⁴⁰ Several methods for their preparation areavailable⁴¹ and N,N-morpholine- andN,N-dimethylmethyleneammoniumchloride were prepared according topublished procedures by cleavage of aminals with acetylchloride.⁴² Theaminals were conveniently synthesized by condensing the amine of choicewith formaldehyde under aqueous conditions.⁴³ The methyleneammoniumchloride salts proved effective and compounds 8a and 8b were isolated in92 and 93% respectively (Table 1, entry 1 and 2). With these excellentresults in hand, the microwave assisted Mannich reaction was now appliedon the sterically more demanding 2-pyridones 4a,b, which requiredanother portion of reactant and heating for an additional 400 s to becompleted. Bearing in mind the pronounced steric impact of theCH₂-naphtyl substituent R² in 4a,b (Table 1) the isolated yields for8c-f (48-66%) were satisfying. It has previously been observed that thedimethylmethyleneammonium salt is less reactive than the correspondingmorpholineammonium salt.⁴¹ This was also confirmed by the resultsobtained in this study (Table 1, entry 3 and 4). Besides resulting ingood to excellent yields, this microwave assisted method offers a muchfaster reaction, 7-14 minutes compared to >22 hours for earlierpublished procedures.^(19,20) Moreover, in contradiction to what wasobserved for the previously described microwave-assisted cyanation andreduction step, the optical purity was not affected as much during thistransformation and tertiary amine 8f was obtained with an ee of 75%(compared to 79% ee for the starting material 4b). TABLE 1 MicrowaveAssisted Mannich Reaction on Substituted 2-pyridones

entry R¹ R² R³ time (s) product yield (%)^(a) 1 Phenyl methyl NMe₂ 4008a 92 2 Phenyl methyl morpholine 400 8b 93 3 Phenyl CH₂-1-naphtyl NMe₂400*2^(b) 8c 48 4 Phenyl CH₂-1-naphtyl morpholine 400*2^(b) 8d 64 5Cyclopropyl CH₂-1-naphtyl NMe₂ 400*2^(b) 8e 55 6 CyclopropylCH₂-1-naphtyl morpholine 400*2^(b) 8f^(c) 66^(a)Yield of the purified product.^(b)An additional amount of 1.1 eq iminium salt was added.^(c)The enantiomeric excess was 75% (compared to 79% ee for the startingmaterial 4b) as determined by chiral HPLC.

Example 2

All reactions were carried out under an inert atmosphere with drysolvents under anhydrous conditions, unless otherwise stated. CH₂Cl₂ wasfreshly distilled from calcium hydride, THF was freshly distilled frompotassium and N-methyl-2-pyrrolidinone (NMP) was dried over 3A molecularsieves.

All microwave reactions were carried out in a monomode reactor usingSmith Process Vials™ (0.5-2.0 or 2.0-5.0 mL filling volume) sealed withTeflon septa and an aluminum crimp top.

TLC was performed on Silica Gel 60 F₂₅₄ (Merck) using UV light detectionand staining with a solution of phosphomolybdic acid and cerium (IV)sulfate in 6% aqueous sulfuric acid or ninhydrin (0.2% in EtOH) and thecompounds were visualized upon heating. Flash column chromatography(eluents given in brackets) employed normal phase silica gel (Matrex, 60A, 35-70 μm, Grace Amicon). Ion-exchange resin (Amberlyst 15, H⁺-form,20-50 mesh) was washed with MeOH prior to use. Organic extracts weredried over sodium sulphate before being concentrated. The ¹H and ¹³C NMRspectra were recorded at 298 K with a Bruker DRX-400 spectrometer inCDCl₃ [residual CHCl₃ (δ_(H) 7.26 ppm) or CDCl₃ (δ_(C) 77.0 ppm) asinternal standard] or MeOH [residual CD₂HOD (δ_(H) 3.31 ppm) or CD₃OD(δ_(C) 49.0 ppm) as internal standard]. IR spectra were recorded on anATI Mattson Genesis Series FTIR™ spectrometer. Optical rotations weremeasured with a Perkin-Elmer 343 polarimeter at 20° C. High-resolutionmass spectra (El or FAB) were recorded on a JEOL JMS-SX 102 massspectrometer. Mass spectra of compound 7c were recorded on a Watersmicromass ZG using electrospray (ES⁺).

(3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (5a). Br₂ (110 uL, 2.1 mmol) was added dropwise to astirred solution of 4a (1.0 g, 2.3 mmol) in AcOH (40 mL) at rt. Afterstirring for 10 min the reaction mixture was concentrated. Purificationby silica gel chromatography (heptane:EtOAc, 1:1) gave 5b as a whitefoam (1.1 g, 93%): [α]_(D)-140 (c 1.0, CHCl₃); IR λ 2921, 2850, 1747,1654, 1581, 1467, 1357, 1224 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (dd,J=7.8, 1.6, 1H), 7.76-7.69 (m, 2H), 7.48-7.32 (m, 3H), 7.20-6.94 (m,6H), 5.78 (dd, J=8.6, 2.6, 1H), 4.38-4.24 (m, 2H), 3.89 (s, 3H), 3.73(dd, J=11.8, 8.6, 1H), 3.50 (dd, J=11.8, 2.6, 1H); ¹³C NMR (100 MHz,CDCl₃) δ 168.1, 157.7, 152.2, 146.2, 136.1, 133.6, 132.5, 131.5, 129.7,129.2, 128.7, 128.6 (broad and splitted), 128.5, 127.0, 125.9, 125.5,125.4, 124.4, 122.8, 117.0, 114.4, 64.9, 53.5, 37.2, 31.7; HRMS (FAB+)calcd for C₂₇H₂₀BrNO₃S 506.0426, obsd 506.0427.

6-Bromo-7-(naphtalen-1-ylmethyl)-5-oxo-8-cyclopropyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (5b). Br₂ (28 uL, 0.54 mmol) was added dropwise to astirred solution of 4b (200 mg, 0.51 mmol) in AcOH (6 mL) at rt. Afterstirring for 30 min the reaction was quenched with 10% aqueous Na₂S₂O₅and the solution was extracted with CH₂Cl₂. The organic layers werewashed with 10% aqueous NaHCO₃ and brine and the resulting aqueouslayers were combined and re-extracted with CH₂Cl₂. The combined organiclayers were dried (Na₂SO₄), filtered and concentrated. Purification bysilica gel chromatography (heptane:EtOAc, 1:4) gave 5b as a white foam(217 mg, 90%). [α]_(D)-177 (c 1.0, CHCl₃); IR λ 2996, 2950, 2356, 1752,1639, 1209, 790; ¹H NMR (400 MHz, CDCl₃) 8.16 (d, J=8.2 Hz, 1H), 7.90(d, J=8.1 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.64-7.51 (m, 2H), 7.31 (t,1H), 6.86 (d, J=6.9 Hz, 1H), 5.72 (dd, J=6.2, 2.5 Hz, 1H), 4.88-4.74 (m,2H), 3.85 (s, 3H), 3.72 (dd, J=11.8, 8.7 Hz, 1H), 3.57-3.51 (dd, J=9.3,2.4 Hz, 1H), 1.44-1.36 (m, 1H), 0.73-0.63 (m, 2H); 0.59-0.50 (m, 2H);¹³C NMR (100 MHz, CDCl₃) 168.3, 157.6, 154.4, 146.6, 133.8, 132.4,131.8, 128.9, 127.1, 126.2, 125.7, 125.6, 123.8, 122.9, 114.7, 114.4,64.0, 53.4, 36.6, 31.6, 12.2, 7.7, 7.3; HRMS (FAB+) calcd forC₂₃H₂₁BrNO₃S 470.0420, obsd 470.0439.

(3R)-6-Bromo-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (5c). By following the procedure described for thepreparation of 5a from 4a, 4c (400 mg, 1.3 mmol) gave 5c as a white foam(500 mg, 98%): [α]_(D)-213 (c 1.0, CHCl₃); IR λ 2998, 2950, 1745, 1639,1579, 1471, 1429, 1211 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.32 (m,3H), 7.24-7.15 (m, 2H), 5.67 (dd, J=8.6, 2.4, 1H), 3.80 (s, 3H), 3.67(dd, J=11.7, 8.6, 1H), 3.42 (dd, J=11.8, 2.4, 1H), 2.10 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 168.1, 157.2, 150.4, 145.1, 136.7, 129.9, 129.6,128.9, 128.8, 128.4, 116.2, 112.5, 64.6, 53.3, 31.6, 22.1; HRMS (FAB+)calcd for C₁₆H₁₅BrNO₃S 378.9956, obsd 378.9947.

(3R)-6-Iodo-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (5d). N-Iodosuccinimide (125 mg, 0.56 mmol) was addedto a stirred solution of 4a (100 mg, 0.23 mmol) in AcOH (1 mL) and TFA(50 μl) at rt. After stirring for 24 hours the reaction mixture waspoured on ice water and neutralized with aqueous saturated NaHCO₃. Theprecipitate was filtered off and purified by silica gel chromatography(heptane:EtOAc, 1:1) giving 5d as a pale orange solid (97 mg, 78%):[α]_(D) 176 (c 0.65, CHCl₃); IR λ 2360, 2344, 1747, 1635, 1570, 1458,1211, 1151, 993 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=7.8, 1H),7.71 (m, 2H), 7.48-7.31 (m, 3H), 7.21-7.01 (m, 5H), 6.97 (d, J=7.5, 1H),5.77 (dd, J=8.7, 2.4, 1H), 4.42-4.28 (m, 2H), 3.87 (s, 3H), 3.71 (dd,J=11.8, 8.7, 1H), 3.43 (dd, J=11.8, 2.4, 1H); ¹³C NMR (100 MHz, CDCl₃) δ168.1, 158.7, 156.5, 147.6, 136.3, 133.5, 132.5, 131.5, 129.6, 129.1,128.6, 128.5 (broad and splitted), 128.3, 127.0, 125.8, 125.5, 125.3,124.5, 122.7, 117.1, 94.3, 65.2, 53.4, 42.0, 31.7; HRMS (FAB+) calcd forC₂₆H₂₁INO₃S 554.0287, obsd 554.0303.

(3R)-6-Cyano-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (6a). CuCN (120 mg, 1.3 mmol) was added to a stirredsolution of 5a (150 mg, 0.30 mmol) in NMP (1.0 mL) at rt. The reactionmixture was heated at 220° C. for 20 min using microwave irradiation andthe solvent was then removed by lyophilisation from deionised water. Theresidue was thoroughly extracted with CH₂Cl₂, dried and concentrated.Purification by silica gel chromatography (heptane:EtOAc, 1:1) gave 6aas a white foam (110 mg, 82%)[α]_(D) −83 (c 1.0, CHCl₃); IR λ 3012,2956, 2217, 1751, 1654, 1486, 1442, 1369 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.79 (d, J=7.8, 1H), 7.70 (d, J=8.1, 1H), 7.62 (d, J=8.2, 1H), 7.47-7.29(m, 3H), 7.19-6.92 (m, 5H), 6.87 (d, J=7.3, 1H), 5.79 (dd, J=8.9, 2.3,1H), 4.41-4.27 (m, 2H), 3.89 (s, 3H), 3.75 (dd, J=11.9, 8.9, 1H), 3.52(dd, J=11.9, 2.3, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.6, 160.7, 158.7,155.2, 134.4, 133.6, 132.4, 131.4, 129.7, 129.2, 128.8 (broad andsplitted), 128.6, 127.6, 126.1, 125.7, 125.3, 125.2, 122.7, 117.1,115.2, 101.3, 64.4, 53.7, 35.3, 31.8; HRMS (EI+) calcd for C₂₇H₂₀N₂O₃S452.1195, obsd 452.1192.

6-Cyano-7-(naphtalen-1-ylmethyl)-5-oxo-8-cyclopropyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (6b). By following the procedure described for thepreparation of 6a from 5a, 5b (100 mg, 0.21 mmol) gave 6b as a whitefoam (78 mg, 88%). [α]_(D)−44 (c 1.0, CHCl₃); IR λ 3004, 2954, 2360,2213, 1747, 1644, 1481, 1213, 1164, 792; ¹H NMR (400 MHz, CDCl₃) 8.12(d, J=8.2 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H),7.62-7.51 (m, 2H), 7.34 (t, 1H), 6,89 (d, J=7.1 Hz, 1H) 5.74 (dd, J=6.7,2.2 Hz, 1H), 4.83-4.70 (m, 2H), 3.86 (s, 3H), 3.76 (dd, J=9.0, 2.9 Hz,1H), 3.58 (dd, J=9.8, 2.2 Hz, 1H), 1.27-1.21 (m, 1H), 0.69-0.65 (m, 2H);0.55-0.53 (m, 2H): ¹³C NMR (100 MHz, CDCl₃) (167.7, 162.9, 158.6, 155.6,133.8, 132.4, 131.7, 128.9, 127.6, 126.4, 125.9, 125.5, 124.1, 122.8,115.2, 114.5, 101.7, 63.5, 53.6, 34.8, 31.7, 11.3, 7.7, 7.2; HRMS (FAB+)calcd for C₂₄H₂₁N₂O₃S 417.1267, obsd 417.1289.

(3R)-6-Cyano-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (6c). By following the procedure described for thepreparation of 6a from 5a, 5c (150 mg, 0.39 mmol) gave 6c as a paleyellow foam (110 mg, 86%): [α]_(D)−161 (c 1.0, CHCl₃); IR λ 3012, 2956,2215, 1749, 1648, 1440, 1365, 1257, 1216 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ7.50-7.39 (m, 3H), 7.25-7.18 (m, 2H), 5.72 (dd, J=8.8, 2.3, 1H), 3.85(s, 3H), 3.72 (dd, J=11.9, 8.8, 1H), 3.51 (dd, J=11.9, 2.3, 1H), 2.21(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.6, 158.8, 158.4, 154.3, 135.0,129.7, 129.5, 129.1 (splitted), 128.9, 116.5, 115.4, 99.5, 64.1, 53.5,31.7, 20.0; HRMS (FAB+) calcd for C₁₇H₁₅N₂O₃S 327.0803, obsd 327.0805.

(3R)-6-Aminomethyl-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (7a). BH₃.Me₂S (250 μL, 2M in THF, 0.5 mmol) was addeddropwise to a solution of 6a (50 mg, 0.11 mmol) in dry THF (4 mL) at rt.The reaction vessel was sealed and heated for 60 s at 100° C. usingmicrowave irradiation. The reaction mixture was cooled to roomtemperature, diluted with CH₂Cl₂, poured onto ice-cold aqueous HCl (1M)and agitated. The pH was then adjusted to ˜10 with 2M aqueous NaOH andthe aqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried and concentrated. The crude product was dissolved in MeOH andswirled with Amberlyst 15. The solid phase was transferred to afiltration funnel and washed with MeOH. The product was released byaddition of 10% NH₃ in MeOH and eluted with MeOH. Concentration of thefiltrate gave 7a as a yellow solid (36 mg, 72%): [α]_(D)−44 (c 0.25,CHCl₃); IR λ 2958, 2854, 1747, 1631, 1492, 1440, 1259, 1214 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 7.83 (d, J=8.2, 1H), 7.78 (d, J=8.1, 1H), 7.71 (d,J=8.7, 1H), 7.54-7.00 (m, 9H), 5.74 (dd, J=8.6, 2.7, 1H), 4.25-4.11 (m,2H), 3.96-3.51 (m, 8H), 3.48 (dd, J=11.8, 2.7, 1H); ¹³C NMR (100 MHz,CDCl₃) δ 168.1, 161.3, 153.5, 148.9, 135.8, 133.8, 133.6, 131.2, 129.7,129.3, 128.7 (splitted), 128.5 (splitted), 127.3, 126.3, 125.9, 125.5,124.4, 123.2, 118.4, 116.6, 64.2, 53.6, 38.0, 33.2, 31.7; HRMS (FAB+)calcd for C₂₇H₂₄N₂NaO₃S 479.1405, obsd 479.1405.

(3R)-6-Aminomethyl-8-cyclopropyl-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (7b). By following the procedure described for thepreparation of 7a from 6a, 6b (46 mg, 0.11 mmol) gave 7b as a yellowsolid (33 mg, 73%): [α]_(D)−64 (c 0.25, CHCl₃); IR λ 2952, 1747, 1631,1569, 1504, 1259, 1214 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=8.2,1H), 7.94-7.27 (m, 5H), 6.81 (d, J=6.8, 1H), 5.67 (d, J=7.3, 1H),4.77-4.56 (m, 2H), 3.96-3.31 (m, 9H), 1.40 (m, 1H), 0.76-0.31 (m, 4H);¹³C NMR (100 MHz, CDCl₃) δ 168.3, 161.1, 155.6 149.5, 133.7, 133.7,131.6, 128.7, 127.3, 126.4, 126.0, 125.5, 123.8, 123.4, 116.9, 115.7,63.4, 53.5, 37.6, 32.6, 31.6, 11.8, 7.2, 7.1; HRMS (FAB+) calcd forC₂₄H₂₅N₂O₃S 421.1586, obsd 421.1593.

(3R)-6-Aminomethyl-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (7c). By following the procedure described for thepreparation of 7a from 6a, 6c (36 mg, 0.11 mmol) gave 7c as a yellowsolid (27 mg, 67%): [α]_(D)−110 (c 0.13, CHCl₃); IR λ 2956, 1747, 1631,1575, 1490, 1442, 1216 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.30 (m,3H), 7.25-7.15 (m, 2H), 5.64 (dd, J=8.5, 2.4, 1H), 3.92-3.69 (m, 7H),3.62 (dd, J=11.5, 8.6, 1H), 3.41 (dd, J=11.6, 2.3, 1H), 2.02 (s, 3H);¹³C NMR (100 MHz, CDCl₃) 6168.8, 161.1, 152.0, 147.8, 136.4, 130.0,129.9, 129.0, 128.9, 128.5, 118.0, 115.3, 64.0, 53.6, 37.9, 31.7, 18.0;MS (ES+) calcd 331 for C₁₇H₂₀N₂O₃S, obsd 331.

6-Dimethylamine-7-(methyl)-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (8a). N,N-Dimethylmethyleneammoniumchloride (140 mg,1.50 mmol) was added to a stirred solution of 4c (200 mg, 0.66 mmol) indry 1,2-dichloroethane (3 mL) at rt. The reaction vessel was sealed andheated for 400 s at 140° C. using microwave irradiation. The reactionmixture was then diluted with CH₂Cl₂, MeOH and concentrated.Purification by silica gel chromatography (ethylacetate→ethylacetate2,5% triethylamine) gave 8a as a white foam (219 mg, 92%). [α]_(D)−163(c 1.0, CHCl₃); IR λ 2939, 2817, 1747, 1631, 1490, 1209, 703; ¹H NMR(400 MHz, CDCl₃) 7.43-7.30 (m, 3H) 7.24-7.16 (m, 2H) 5.64 (dd, J=8.6,2.5 Hz, 1H) 3.78 (s, 3H) 3.59 (dd, J=11.7, 8.7 Hz, 1H) 3.47 (d, J=12.2Hz, 1H) 3.38 (dd, J=11.7, 2.5 Hz, 1H) 3.31 (d, J=12.2 Hz, 1H) 2.25 (s,6H) 2.0 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) 168.6, 161.5, 150.7, 144.2,137.3 130.0, 129.7, 128.7, 128.6, 127.9, 122.2, 116.7, 64.0, 54.2, 53.1,45.4, 31.3; 17.5; IR λ 2939, 2817, 1747, 1631, 1490, 1209, 703; HRMS(FAB+) calcd for C₁₉H₂₃N₂O₃S 359.1429, obsd 359.1426.

6-Morpholine-7-(methyl)-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (8b). By following the procedure described for thepreparation of 8a from N,N-Dimethylmethyleneammoniumchloride and 4c,N,N-Morpholinemethyleneammoniumchloride and 4c (200 mg, 0.66 mmol) gave8b as a white foam (249 mg, 93%). [α]_(D)−161 (c 1.0, CHCl₃); IR λ 2955,2850, 2360, 1749, 1631, 1490, 1112, 703; ¹H NMR (400 MHz, CDCl₃)7.45-7.34 (m, 3H), 7.26-7.20 (m, 2H), 5.67 (dd, J=8.6, 2.6 Hz, 1H), 3.82(s, 3H), 3.70-3.64 (m, 4H), 3.63-3.53 (m, 2H), 3.46-3.38 (m, 2H),2.53-2.48 (m, 4H), 2.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) 168.5, 161.5,151.3, 144.4, 137.2, 130.0, 129.8, 128.7, 128.6, 120.0, 121.1, 116.7,67.1, 64.0, 53.4, 53.1, 31.8, 31.3, 17.5; HRMS (FAB+) calcd forC₂₁H₂₅N₂O₄S 401.1535, obsd 401.1536.

6-Dimethylamine-7-(naphtalen-1-ylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (8c). N,N-Dimethylmethyleneammoniumchloride (144 mg,1.54 mmol) was added to a stirred solution of 4a (300 mg, 0.70 mmol) indry 1,2-dichloroethane (3 mL) at rt. The reaction vessel was sealed andheated for 140° C. for 400 s using microwave irradiation, moreN,N-Dimethylmethyleneammoniumchloride (72 mg, 0.77 mmol) was added, andthe reaction mixture was heated for another 400 s at 140° C. Thereaction mixture was then diluted with CH₂Cl₂, MeOH and concentrated.Purification by silica gel chromatography (ethylacetate→ethylacetate2,5% triethylamine) gave 8c as a white foam (148 mg, 48%). [α]_(D)−151(c 1.0, CHCl₃); IR λ 3048, 2940, 2817, 2767, 1747, 1633, 1490, 790, 701;¹H NMR (400 MHz, CDCl₃) 7.83-7.77 (m, 2H) 7.67 (d, J=8.2 Hz, 1H)7.45-7.30 (m, 3H) 7.12-6.99 (m, 6H) 5.76 (dd, J=8.6, 2.6 Hz, 1H) 4.44(d, J=16 Hz, 1H) 4.32 (d, J=16 Hz, 1H) 3.85 (s, 3H) 3.66 (dd, J=11.8,8.7 Hz, 1H) 3.44 (dd, J=11.8, 8.7 Hz, 1H) 3.30-3.20 (m, 2H) 2.21 (s,6H); ¹³C NMR (100 MHz, CDCl₃) 168.5, 161.8 152.2, 145.5, 136.5, 134.5,133.3, 131.6, 129.8, 129.2, 128.4, 128.3, 128.2, 127.9, 126.7, 125.8,125.4, 125.3, 124.2, 123.4, 122.8, 117.2, 64.2, 53.9, 53.1, 45.6, 31.8,31.3; HRMS (FAB+) calcd for C₂₉H₂₉N₂O₄S 485.1893, obsd 485.1866.

6-Morpholine-7-(naphtalen-1-ylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (8d). N,N-Morpholinemethyleneammoniumchloride (209 mg,1.54 mmol) was added to a stirred solution of 4a (300 mg, 0.70 mmol) indry 1,2-dichloroethane (3.2 mL) at rt. The reaction vessel was sealedand heated for 400 s at 140° C. using microwave irradiation, moreN,N-Morpholinemethyleneammoniumchloride (105 mg, 0.77 mmol) was addedand the reaction mixture was heated for another 400 s at 140° C. Thereaction mixture was then diluted with CH₂Cl₂, MeOH and concentrated.Purification by silica gel chromatography (ethylacetate→ethylacetate2,5% triethylamine) gave 8d as a yellow foam (237 mg, 64%). [α]_(D)−98(c 1.0, CHCl₃); IR λ 2952, 2846, 1749, 1633, 1490, 1112, 701 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.84-7.79 (m, 2H) 7.68 (d, J=8.2 Hz, 1H)7.46-7.38 (m, 2H) 7.34 (t, 1H) 7.17-7.04 (m, 6H) 5.75 (dd, J=8.6, 2.7Hz, 1H) 4.49 (d, J=15.9, 1H) 4.34 (d, J=15.9 Hz, 1H) 3.87 (s, 3H) 3.69(dd, J=11.8, 8.7 Hz, 1H) 3.56-3.50 (m, 4H) 3.46 (dd, J=11.8, 2.7 Hz, 1H)3.32 (m, 2H) 2.40-2.30 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 161.9,153.1, 145.7, 136.5, 134.8, 133.4, 131.7, 129.9, 129.3, 128.6, 128.4,128.4, 128.0, 126.7, 125.8, 125.5, 125.4, 124.4, 122.8, 122.3 117.5,66.9, 64.3, 53.5, 53.2, 53.2, 32.0, 31.3; HRMS (FAB+) calcd forC₃₁H₃₁N₂O₄S 527.1999, obsd 527.2008.

6-Dimethylamine-7-(naphtalen-1-ylmethyl)-5-oxo-8-cyclopropyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (8e). By following the procedure described for thepreparation of 8c from 4a, 4b (200 mg, 0.51 mmol) gave 8e as a whitefoam (125 mg, 55%). [α]_(D)−177 (c 1.0, CHCl₃); IR λ 2939 2948, 2817,2767, 1747, 1633, 1579, 1498, 1211, 792, 773; ¹H NMR (400 MHz, CDCl₃)8.23 (d, J=8.4 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H) 7.69 (d, J=8.2 Hz, 1H)7.60-7.48 (m, 2H) 7.31-27 (m, 1H) 6.82 (d, J=6.8 Hz, 1H) 5.69 (dd,J=8.7, 2.5 Hz, 1H) 4.83-4.80 (m, 2H) 3.81 (s, 3H) 3.67 (dd, J=11.8, 8.7Hz, 1H) 3.48 (dd, J=8.7, 2.6 Hz, 1H) 3.30-3.19 (m, 2H) 2.19 (s, 6H)1.34-1.24 (m, 1H) 0.63-0.53 (m, 4H);

¹³C NMR (100 MHz, CDCl₃) 168.7, 161.7, 154.9, 145.9, 134.5, 133.5,131.9, 128.6, 128.6, 126.0, 125.6, 125.5, 123.7, 123.6, 123.0, 114.2,63.4, 53.7, 53.0, 45.5, 31.2, 31.2, 11.5, 7.2, 7.0; HRMS (FAB+) calcdfor C₂₆H₂₉N₂O₃S 449.1893, obsd 449.1887.

6-Morpholine-7-(naphtalen-1-ylmethyl)-5-oxo-8-cyclopropyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (8f). By following the procedure described for thepreparation of 8d from 4a, 4b (400 mg, 1.02 mmol) gave 8f as a yellowfoam (331 mg, 66%). [α]_(D)−110 (c 1.0, CHCl₃); IR λ 2956, 2844, 1749,1631, 1496, 1110, 792, 773, 728; ¹H NMR (400 MHz, CDCl₃) 8.20 (d, J=8.4Hz, 1H), 7.87 (d, J=7.5 Hz, 1H) 7.70 (d, J=8.2 Hz, 1H) 7.61-7.48 (m, 2H)7.29 (t, 1H) 6.84 (d, J=7.1 Hz, 1H) 5.68 (dd, J=8.7, 2.6 Hz, 1H)4.87-4.78 (m, 2H) 3.82 (s, 3H) 3.69 (dd, J=11.8, 8.7 Hz, 1H) 3.52-3.45(m, 5H) 3.32 (m, 2H) 2.34 (m, 4H) 1.40-1.32 (m, 2H) 0.68-0.53 (m, 4H);¹³C NMR (100 MHz, CDCl₃) 168.6, 161.8, 155.5, 146.1, 134.7, 133.5,131.9, 128.7, 126.6, 126.0, 125.6, 125.4, 123.6, 122.9, 122.4, 114.5,66.9, 63.4 53.3, 53.1, 52.9, 31.4, 31.2, 11.5, 7.3, 7.0; HRMS (FAB+)calcd for C₂₉H₃₁N₂O₄S 491.1999, obsd 491.1998.

8-Cyclopropyl-6formyl-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5h-thiazolo[3,2-a]pyridine-3-carboxylicacid methyl ester (2). 1 (500 mg, 1,23 mmol) was quickly added to astirred solution of Vilsmeier's salt (C⁻Me2N═CHCl) (630 mg, 4,93 mmol)in acetonitrile (10 ml). After refluxing for 3 h the solution wasconcentrated then diluted with CH₂Cl₂ and quenched with sat NaHCO₃ (aq).The aqueous phase was extracted with CH₂Cl₂ and the combinedorganic-phases were dried over Na₂SO₄(s) filtered and concentrated.Purification by filtering through a short silica plug (EtOAc) gave 2a asyellow foam (532 mg, 99%).[α]_(D)−16.4°; ¹H-NMR (400 MHz, CDCl₃), 10.39(s, 1H), 8.19 (d, J=8.3, 1H), 7.86 (d, J=8.1, 1H), 7.69 (d, J=8.3, 1H),7.59 (t, J=7.6, 1H), 7.52 (t, J=7.4, 1H), 7.27 (t, J=7.7, 1H), 6.77 (d,J=7.0, 1H), 5.75 (dd, J=9.0, 2.6, 1H), 5.21 (d, J=14.8, 1H), 5.09 (d,J=14.8, 1H), 3.87 (s, 3H), 3.69-3.79 (m, 1H), 3.54 (dd, J=12.0, 2.5,1H), 1.30-1.38 (m, 1H), 0.64-0.75 (m, 2H), 0.50-0.58 (m, 2H); ¹³C-NMR(100 MHz, CDCl₃), 190.7, 168.1, 162.2, 160.8, 156.7, 134.5, 133.6,132.0, 128.7, 126.7, 126.0, 125.6, 125.3, 123.1, 123.0, 118.9, 115.5,63.3, 53.4, 31.4, 31.4, 11.1, 7.8, 7.2; IR, 2952, 2362, 2246, 1749,1635, 1475, 1409, 1216, 1160, 728.

General procedure for reductive anination. 1.0 eq of amine is added to astirred solution of aldehyde in CH₂Cl₂:MeOH and 3 A mol sieves at 0° C.and is allowed to stir for 30 min. 1.8 eq of Sodiumtriacetoxyborohydride is then added and the mixture is allowed to attainrt and stir for 3 hours. Washed with sat NaHCO₃ (aq). The aqueous phaseis extracted with CH₂Cl₂ and the combined organic-phases were dried overNa₂SO₄(s). Purification by column chromatography yields theaminomethylated 2-pyridones 3a-f.

(3R)-6-(Benzylamino-methyl)-8-cyclopropyl-7-(Naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-5h-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (3b). ¹H-NMR (400 Mhz, CDCl₃) 8.08 (d, J=8.32 Hz, 1H,ArH), 7.88 (d, J=7.87 Hz, 1H, ArH), 7.71 (d, J=8.14 Hz 1H, ArH),7.64-7.47 (m, 2H, ArH) 7.35-7.07 (m, 6H, ArH) 6.83 (d, J=6.86 Hz, 1H,ArH), 5.68 (d, J=7.50 Hz, 1H, CHCO₂Me), 4.66 (d, J=16.47 Hz, 1H,Nph-CH₂), 4.57 (d, J=16.47 Hz, 1H, Nph-CH₂) 3.83 (s, 3H, CH₃) 3.77-3.38(m, 7H, SCH₂, PhCH₂, BnNHCH₂) 1.46-1.33 (m, 1H, CH-cyclopropyl)0.70-0.44 (m, 4H, CH2-cyklopropyl) 13C-NMR (100 Mhz, CDCl₃) δ 168.67,161.52, 153.13, 146.01, 139.55, 134.42, 133.61, 131.74, 128.76, 128.21,128.13, 126.94, 126.81, 126.21, 125.77, 125.50, 124.35, 123.99, 123.04,114.53, 63.31, 53.46, 53.23, 45.31, 31.93, 31.42, 29.65, 11.79, 7.42,7.12.

(3R)-8-Cyclopropyl-6-hydroxymethyl-7-(Naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-5h-thiazolo[3,2-a]pyridine-3-carboxylicAcid Methyl Ester (4). The formylated 2-pyridone 2 (100 mg, 0.239 mmol)was dissolved in tetrahydrofuran (3.30 mL) at 0° C. Then 2M BH₃.DMS.THF(0.131 mL, 0.262 mmol) was added dropwise during 15 min. The mixture wasthen stirred in room temperature during 1 h, quenched with methanol andconcentrated twice from methanol. The residue was purified through flashcolumn chromatography (CH₂Cl₂:MeOH, 9:1). Co-concentration from CH₂Cl₂(×2) resulted in 4 as white foam (80.6 mg, yield: 80%). ¹H-NMR (400 Mhz,CDCl₃) δ 8.16 (d, J=8.23 Hz, 1H, ArH), 7.87 (d, J=7.96 Hz, 1H, ArH),7.71 (d, J=8.14 Hz 1H, ArH), 7.64-7.48 (m, 2H, ArH) 7.30 (m, 1H, ArH)6.83 (d, J=6.95 Hz, 1H, ArH), 5.68 (d, J=7.04 Hz, 1H, CHCO2Me), 4.72 (d,J=16.28 Hz, 1H, Nph-CH2), 4.61 (d, J=16.28 Hz, 1H, Nph-CH2) 4.58-4.36(m, 2H, CH₂OH) 3.84 (s, 3H, CH₃) 3.76-3.62 (m, 2H, SCH₂, OH) 3.60-3.50(m, 1H, SCH₂) 1.46-1.34 (m, 1H, CH-cyclopropyl) 0.65 (ss, 2H,CH₂-cyklopropyl) 0.51 (ss, 2H, CH₂-cyklopropyl) ¹³C-NMR (100 Mhz, CDCl₃)δ 168.61, 161.87, 152.08, 146.62, 134.11, 133.76, 131.77, 128.94,127.17, 126.37, 125.92, 125.66, 125.63, 124.26, 122.98, 114.93, 63.27,58.78, 53.40, 31.77, 31.58, 11.81, 7.53, 7.20.

(3R)-8-Cyclopropyl-7-(Naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3,6-dicarboxylicAcid 3-Methyl Ester (5). To a solution of 2 (100 mg, 0.239 mmol) indimethylsulfoxide (2.40 mL), NaH2PO4 (66.0 mg, 0.478 mmol), dissolved inwater (0.960 mL), was added dropwise at room temperature. The mixturewas then kept on ice and NaClO₂ (86.0 mg, 0.956 mmol) dissolved in water(0.480 mL), was added dropwise during 30 min. A white precipitateformed. The reaction mixture was stirred in room temperature for 1 h andthen poured into a separation funnel containing ice-cooled 1M HCl. Theaqueous phase was extracted with CH₂Cl₂ and the combined organic phasesconcentrated. The residue was dissolved in H₂O:MeCN, 8:2 and freezedried to yield 5 as a white powder (102 mg, yield: 98%). ¹H-NMR (400Mhz, CDCl₃) δ 14.60 (s, 1H, CO₂H), 8.21 (d, J=8.32 Hz, 1H, ArH), 7.85(d, J=7.68 Hz 1H, ArH), 7.67 (d, J=8.14 Hz, 1H, ArH) 7.61-7.45 (m, 2H,ArH) 7.30-7.21 (m, 1H, ArH), 6.69 (d, J=6.72 Hz, 1H, ArH), 5.78 (d,J=8.42 Hz, 1H, ArH), 5.51 (d, J=14.55 Hz, 1H, Nph-CH₂) 5.37 (d, J=14.55Hz, 1H, Nph-CH₂) 3.87 (s, 3H, CH₃) 3.82-3.72 (m, 1H, SCH₂) 3.63-3.54 (m,1H, SCH₂) 1.44-1.32 (m, 1H, CH-cyclopropyl) 0.81-0.64 (m, 2H) 0.56 (sd,2H, CH₂-cyclopropyl) ¹³C-NMR (100 Mhz, CDCl₃) δ 167.59, 165.24, 165.09,163.75, 154.33, 134.92, 133.84, 132.16, 128.83, 126.78, 126.15, 125.76,125.51, 123.40, 123.23, 118.68, 112.72, 64.10, 53.84, 33.35, 31.58,12.10, 8.35, 7.67.

Example 3

Protocol for Hemagglutination Assay

The Hemagglutination Assay was carried out according to the followingsteps:

1. The bacterial culture or protein was induced with either IPTG orarabinose for an optimal amount of time.

2. Next, blood was washed with PBS (by adding PBS, spinning, pouring offsupernatant, then adding PBS) until the supernatant was clear of redcolor.

3. The blood was then brought to optical density of 2.0 at a wavelengthof 640 nm to absorbance of 1.8-2.0 (PBS was added until the right OD wasobtained).

Steps 4 & 5 were completed for bacteria. When proteins were used, thesetwo steps were ignored.

4. The bacteria was brought to optical density of 2.0 at 600 nm to theabsorbance of 0.9-1.0 in PBS (the induced culture was spun down firstand then brought up in PBS to OD).

5. A total of 3 ml of bacterial culture was spun down in an ependorfftube. The bacterial pellete was then resuspended in 100 micro liter PBS.

6. 25 micro liter of PBS was placed in every well of a V-bottommicrotiter plate.

7. Next, 25 micro liters of appropriate bacteria (or protein) was addedin the first well of each row. Typically at least triplicate of the samebacteria was used on the same plate.

8. With a multi-channel pipet a 2-fold serial dilution was done of thebacterial culture (or protein) by completing the following steps:

a. the bacteria and PBS were mixed in first well.

b. 25 micro liters were removed and put in the next well;

c. the contents of the wells were mixed;

d. steps b and c were repeated for serial dilution.

9. 25 micro liters of the appropriate blood were added to each row(changing tips in between). The wells were taped lightly to evenlydistribute the liquid in the wells.

10. The wells were covered and placed in 4 degree Celcius cold roomuntil the plate was read.

The results of this assay are disclosed in Table A.

Example 4

Infection of Bladder Cells in vitro (Adherence Assay)

The infection of bladder cells in vitro was carried out according to thefollowing steps:

Preparation of Tissue Culture Cells (Type 5637 Bladder Cell Line)

1. Place 1 ml of RPMI/10% FBS containing 1:20 dilution of 5637 cells ineach well of 24 well plate.

2. Place in incubator for 3 days or until confluent growth.

Preparation of Bacterial Cells (Strains NU14 and UTI89)

1. Inoculate 20 ml of LB containing NU14 with a single colony or a loopfrom a frozen stock to a 250 ml flask.

2. Static growth at 37° C. for 2 days to induce pili production.

3. Harvest cells at 4,000×g for 10 minutes.

4. Resuspend in 5 ml of PBS (−109 cells/ml)

5. Dilute 1:100 in PBS.

Infection of Tissue Culture Cells In Vitro

1. Wash each well with PBS MgCl₂/CaCl₂.

2. Place 1 ml of fresh medium to each well.

3. Add 10 μl of bacterial cells to each well. Triplicate plates.

4. Spin plate at 1800 rpm for 5 minutes.

5. View under 40× to see—2-3 bacterial cells/epithelial cell.

6. Place in lower incubator for 2 hours.

7. Wash two plates 5× with PBS MgCl₂/CaCl₂. Lyse by addition of 0.1%sarkosyl/0.5% glucose/PBS-MgCl₂/CaCl₂ one set and dilute for CFU.

The results of this assay are disclosed in Table A.

Example 5

Biofilm Assay

The Biofilm Assay was carried out according to the following steps:

Day 1 Set Up Biofilm Growth on PVC Plates

1. Sterilize PVC plates (96-well round bottom polyvinyl chloride [PVC]plates; Falcon #353911) and PVC Lids (Falcon #353913) in tissue culturehood under UV irradiation for at least 30 min.

2. Make dilution (from overnight cultures) or suspension (from eithercolonies on plates or freezer stocks) of bacterial cultures. Make enoughof bacterial cultures for the number of wells needed. Bacterial cultureneed to be very dilute: at least 1:1,000 fold dilution from overnightcultures or a small quantity from colonies or freezer stocks.

3. Add 100 μl of bacterial cultures into each well. Make sure to have 1well with LB alone as negative control and 1 well without anything forblank.

4. Cover plates with lids and leave plates undisturbed at roomtemperature for 48 hrs.

Day 3 Assay Biofilm With Crystal Violet Stain

Wash Biofilm Plates

5. Prepare enough PBS (w/out Mg²⁺ Ca²⁺) to wash biofilm plates (need atleast 3 L PBS for 1-5 plates). Could use mpH₂O instead of PBS.

6. Get a clean 4 L plastic beaker. Cover the bench with a large piece ofabsorbent pad.

7. Fill 3 containers (large enough to dip the 96-well plates in) withPBS.

8. Start washing a biofilm plate by dumping out bacterial cultures intothe beaker. (Treat contents in this beaker as biohazard. Need to bleachthe content before emptying it into drain.)

9. Fill the biofilm plate in the first PBS container and shake off PBSin the beaker. Rinse the biofilm 1× in the first PBS container. Put thebiofilm plate into the second PBS container and rinse 2×.

10. Put the biofilm plate in the third PBS container and let sit.

11. Proceed to wash a second biofilm plate if there are any.

12. While the second biofilm plate is in the second container, rinse thefirst biofilm plate 1× and remove it from PBS. Decant residual PBS bybanging the plate on paper towels on the bench. Leave the plateup-side-down on a clean paper towel and let the plate dry.

13. Put the second biofilm plate into the third PBS container and letsit.

14. Proceed to wash a third biofilm plate if applicable.

15. Repeat steps 8-14 until all plates are washed.

16. Let washed biofilm plates air-dry for at least 15 min.

Crystal Violet Stain and Wash

17. Fill 4 containers (large enough to dip the 96-well plates in) withPBS.

18. With a multi-channel pipet, add 125 μl of 1% Crystal Violet (inmpH₂O). Stain biofilm plates sequentially for 10 min. (not more than 15min). Give at least 2 minute break in-between staining each plates. Ifmore than 4 biofilm plates, might want to consider staining and washingthem in batches.

19. Start washing biofilm plates as above.

20. Let the washed plates air-dry for 10 minor so.

Assay Crystal Violet Stain

21. While plates are drying, prepare EtOH:Acetone (80:20) solubilizationsolution. Need 150 μl/well.

Get new flat-bottom 96-well plates (use ELISA plates; Immunon-4).

Set up the Plate Reader.

22. Add 150 μl of solubilization solution into each well to dissolvestained biofilms. Be sure not to splatter to other wells. Change tips ifpipet tips become contaminated with crystal violet.

23. After adding solubilization solution to all wells, transfer 100 μlof the dissolved biofilms to a new flat-bottom plate, except the wellintended for blank. Change tips in between transfer. Add 100 μl of freshsolubilization solution into the blank well.

24. Proceed immediately to the Plate Reader and read the absorbance ofthe plate at 600 nm.

25. Continue steps 22-24 for each plate.

The results of this assay are disclosed in Table A. TABLE A PilicideData From Assays Adherence Assay Bioflim Assay Compound HA Titer % ofWild Type % of Wild Type NU14 2⁸ 100% 100%

2⁸ 97.6% 73.1% C₁₈H₁₉LiN₂O₃S Exact Mass: 350.1276 Mol. Wt.: 350.3611

2⁴ 21.8% 6.9% C₂₈H₂₅LiN₂O₃S Exact Mass: 476.1746 Mol. Wt.: 476.5157

2⁴ 14.3% 6.8% C₃₁H₂₈LiN₂O₄S Exact Mass: 531.1930 Mol. Wt.: 531.5710

2³ 12.2% 8.3% C₂₇H₂₇LiN₂O₄S Exact Mass: 482.1852 Mol. Wt.: 482.5203

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1. An amino methylated 2-pyridinone corresponding to Formula I or a saltthereof:

wherein R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, heterocyclo or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen; R₄ and R₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided at leastone of R₄ and R₅ is other than hydrogen; and the “Z” ring contains 5 to7 ring atoms selected from the group consisting of carbon, oxygen,nitrogen and sulfur, provided (i) at least 4 of the ring atoms arecarbon when the “Z” ring contains 7 ring atoms, and (ii) at least 3 ofthe ring atoms are carbon when the “Z” ring contains 5 or 6 ring atoms.2. The amino methylated 2-pyridinone of claim 1, corresponding toFormula II or a salt thereof:

wherein R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl or heterocyclo or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen; R₄ and R₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided at leastone of R₄ and R₅ is other than hydrogen; X₁ is a bond, carbon; oxygen,nitrogen, or sulfur; X₂ is a bond, carbon; oxygen, nitrogen, or sulfur;X₃ and X₄ are independently carbon; oxygen, nitrogen, or sulfur; X₅ iscarbon or nitrogen; each X₁₁, when present, is an electron pair,hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, oxo, haloor acyl; each X₂₂, when present, is an electron pair, hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, or oxo; each X₃₃ andX₄₄ is independently an electron pair, hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, or oxo; X₅₅ is —CH₂OX₅₅₅,—CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅, —CHO, —B(OH)₂, or —PO(OH)₂; andX₅₅₅ is hydrogen or other cation, hydrocarbyl, substituted hydrocarbyl,or heterocyclo; provided, however, (i) X₁₁ or X₂₂ is not present when X₁or X₂, respectively, is a bond; (ii) no more than three of X₁, X₂, X₃,X₄ and X₅ are oxygen, nitrogen or sulfur when the “Z” ring contains 6 or7 ring atoms, and (iii) no more than two of X₁, X₂, X₃, X₄ and X₅ areoxygen, nitrogen or sulfur when the “Z” ring contains 5 ring atoms. 3.The amino methylated 2-pyridinone of claim 1 corresponding to FormulaIII or a salt thereof:

wherein R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl or heterocyclo or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen; R₄ and R₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided at leastone of R₄ and R₅ is other than hydrogen; X₂ is a bond, carbon; oxygen,nitrogen, or sulfur; X₃ and X₄ are independently carbon; oxygen,nitrogen, or sulfur; X₅ is carbon or nitrogen; each X₂₂, when present,is an electron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl,heterocyclo, or oxo; each X₃₃ and X₄₄ is independently an electron pair,hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, oxo, haloor acyl; X₅₅ is —CH₂OX₅₅₅, —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅, —CHO,—B(OH)₂, or —PO(OH)₂; and X₅₅₅ is hydrogen or other cation, hydrocarbyl,substituted hydrocarbyl, or heterocyclo; provided, however, (i) X₂₂ isnot present when X₂ is a bond; and (ii) no more than two of X₂, X₃, X₄and X₅ are oxygen, nitrogen or sulfur when the “Z” ring contains 5 ringatoms.
 4. The amino methylated 2-pyridinone of claim 1 corresponding toFormula IV or a salt thereof:

wherein R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl or heterocyclo or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen; R₄ and R₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided at leastone of R₄ and R₅ is other than hydrogen; X₃ and X₄ are independentlycarbon; oxygen, nitrogen, or sulfur; X₅ is carbon or nitrogen; each X₃₃is independently an electron pair, hydrogen, hydrocarbyl, substitutedhydrocarbyl, heterocyclo, or oxo; each X₄₄ is independently an electronpair, hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, oxo,halo or acyl; X₅₅ is —CH₂OX₅₅₅, —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅,—CHO, —B(OH)₂, or —PO(OH)₂; and X₅₅₅ is hydrogen or other cation,hydrocarbyl, substituted hydrocarbyl, or heterocyclo; provided, however,no more than one of X₃, X₄ and X₅ is oxygen, nitrogen or sulfur when the“Z” ring contains 5 ring atoms.
 5. The amino methylated 2-pyridinone ofclaim 1 corresponding to Formula Va or a salt thereof:

wherein R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl or heterocyclo or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen; R₄ and R₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided at leastone of R₄ and R₅ is other than hydrogen; X₃ is carbon; oxygen, nitrogen,or sulfur; X₅ is carbon or nitrogen; each X₃₃ is independently anelectron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl,heterocyclo, or oxo; each X₄₄ is hydrogen, hydrocarbyl, halo or acyl;X₅₅ is —CH₂OX₅₅₅, —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅, —CHO, —B(OH)₂,or —PO(OH)₂; and X₅₅₅ is hydrogen or other cation, hydrocarbyl,substituted hydrocarbyl, or heterocyclo; provided, however, no more thanone of X₃ and X₅ is oxygen, nitrogen or sulfur.
 6. The amino methylated2-pyridinone of claim 1 corresponding to Formula VIa or a salt thereof:

wherein R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl or heterocyclo or, in combination with the nitrogen atom towhich they are bonded, form a heterocyclo, provided at least one of R₂and R₃ is other than hydrogen; R₄ and R₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided at leastone of R₄ and R₅ is other than hydrogen; X₄₄ is hydrogen, hydrocarbyl,substituted hydrocarbyl, heterocyclo, oxo, halo or acyl; X₅₅ is—CH₂OX₅₅₅, —CH(CO₂X₅₅₅)₂, —CH₂CO₂X₅₅₅, —CO₂X₅₅₅, —CHO, —B(OH)₂, or—PO(OH)₂; and X₅₅₅ is hydrogen or other cation, hydrocarbyl, substitutedhydrocarbyl, or heterocyclo.
 7. The amino methylated 2-pyridinone of anyof claim 6 wherein X₄₄ is hydrogen, alkyl, halo, —C(O)R₄₄ or—C(O)N(R₄₄)₂ and each R₄₄ is independently hydrogen, alkyl or aryl. 8.The amino methylated 2-pyridinone of claim 6 wherein X₅₅ is —CO₂X₅₅₅. 9.The amino methylated 2-pyridinone of claim 8 wherein X₅₅₅ is hydrogen,alkyl, or an alkalie metal.
 10. The amino methylated 2-pyridinone ofclaim 1 wherein (i) R₂ and R₃ are independently hydrogen, hydrocarbyl,substituted hydrocarbyl or heterocyclo, provided at least one of R₂ andR₃ is other than hydrogen and (ii) each X₁₁, when present, is anelectron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl,heterocyclo, or oxo.
 11. The amino methylated 2-pyridinone of claim 6wherein (i) R₂ and R₃ are independently hydrogen, hydrocarbyl,substituted hydrocarbyl or heterocyclo, and (ii) X₄₄ is hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, or oxo.
 12. The aminomethylated 2-pyridinone of claim 6 wherein R₂ is alkyl.
 13. The aminomethylated 2-pyridinone of claim 6 wherein R₂ and R₃, in combinationwith the nitrogen atom to which they are bonded from a heterocyclo. 14.The amino methylated 2-pyridinone of claim 6 wherein R₄ is alkyl oraryl.
 15. The amino methylated 2-pyridinone of claim 6 wherein R₅ isalkyl.
 16. A compound having the formula

wherein R1, R2, and R3, in combination, are selected from thecombinations identified in the following table as combinations 8a-8f:Combination No. R¹ R² R³ 8a phenyl methyl NMe₂ 8b phenyl methylmorpholine 8c phenyl CH₂-1-naphtyl NMe₂ 8d phenyl CH₂-1-naphtylmorpholine 8e cyclopropyl CH₂-1-naphtyl NMe₂  8f^(c) cyclopropylCH₂-1-naphtyl morpholine


17. A process for inhibiting adherence of a bacteria to a host cell, theprocess comprising treating the bacteria with a compound of claim 1 or asalt thereof.
 18. The process of claim 17, the comprising treating thebacteria with a compound of claim 7.